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  • 1. Anantharaman, Devasena
    et al.
    Gheit, Tarik
    Waterboer, Tim
    Halec, Gordana
    Carreira, Christine
    Abedi-Ardekani, Behnoush
    McKay-Chopin, Sandrine
    Zaridze, David
    Mukeria, Anush
    Szeszenia-Dabrowska, Neonila
    Lissowska, Jolanta
    Mates, Dana
    Janout, Vladimir
    Foretova, Lenka
    Bencko, Vladimir
    Rudnai, Peter
    Fabianova, Eleonora
    Tjonneland, Anne
    Travis, Ruth C
    Boeing, Heiner
    Quiros, J Ramon
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krogh, Vittorio
    Bueno-de-Mesquita, H Bas
    Kotanidou, Anastasia
    Clavel-Chapelon, Francoise
    Weiderpass, Elisabete
    Johansson, Mattias
    Pawlita, Michael
    Scelo, Ghislaine
    Tommasino, Massimo
    Brennan, Paul
    No causal association identified for human papillomavirus infections in lung cancer2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3525-3534Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer. (C) 2014 AACR.

  • 2.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Johansson, David
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro.2007In: Acta Oncologica, ISSN 0284-186X, Vol. 46, no 7, p. 951-960Article in journal (Refereed)
  • 3. Baglietto, Laura
    et al.
    Ponzi, Erica
    Haycock, Philip
    Hodge, Allison
    Bianca Assumma, Manuela
    Jung, Chol-Hee
    Chung, Jessica
    Fasanelli, Francesca
    Guida, Florence
    Campanella, Gianluca
    Chadeau-Hyam, Marc
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ala, Ugo
    Provero, Paolo
    Wong, Ee Ming
    Joo, Jihoon
    English, Dallas R
    Kazmi, Nabila
    Lund, Eiliv
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    Barrdahl, Myrto
    Sandanger, Torkjel M
    Southey, Melissa C
    Giles, Graham G
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Vineis, Paolo
    Polidoro, Silvia
    Relton, Caroline L
    Severi, Gianluca
    DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 1, p. 50-61Article in journal (Refereed)
    Abstract [en]

    DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled  = 4 × 10(-17) ), cg03636183 in the F2RL3 gene (p-valuepooled  = 2 × 10 (- 13) ), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled  = 7 × 10(-16) and 1 × 10(-11) respectively), cg06126421 in 6p21.33 (p-valuepooled  = 2 × 10(-15) ) and cg23387569 in 12q14.1 (p-valuepooled  = 5 × 10(-7) ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity  ≤ 1.8 x10 (- 7) ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

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  • 4. Battram, Thomas
    et al.
    Richmond, Rebecca C.
    Baglietto, Laura
    Haycock, Philip C.
    Perduca, Vittorio
    Bojesen, Stig E.
    Gaunt, Tom R.
    Hemani, Gibran
    Guida, Florence
    Carreras-Torres, Robert
    Hung, Rayjean
    Amos, Christopher, I
    Freeman, Joshua R.
    Sandanger, Torkjel M.
    Nøst, Therese H.
    Nordestgaard, Børge G.
    Teschendorff, Andrew E.
    Polidoro, Silvia
    Vineis, Paolo
    Severi, Gianluca
    Hodge, Allison M.
    Giles, Graham G.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mattias
    Smith, George Davey
    Relton, Caroline L.
    Appraising the causal relevance of DNA methylation for risk of lung cancer2019In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 48, no 5, p. 1493-1504Article in journal (Refereed)
    Abstract [en]

    Background: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.

    Methods: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer.

    Results: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk.

    Conclusions: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.

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  • 5. Bjerkvig, Rolf
    et al.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. NorLux Neuro-Oncology Laboratory, Centre de Recherche Public Santé, 84, Val Fleuri, L-1526 Luxembourg.
    Miletic, Hrvoje
    Niclou, Simone P
    Cancer stem cells and angiogenesis2009In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 19, no 5, p. 279-284Article, review/survey (Refereed)
    Abstract [en]

    Most cancers contain tumor cells that display stem cell-like characteristics. How and when such cells appear in tumors are not clear, but may involve both stochastic as well as hierarchical events Most. likely, tumor cells that display stem cell-like characteristics can undergo asymmetric cell division giving rise to tumor cells that trigger angiogenic programs. As normal stem cells the cancer stem-like cells seem to adapt to hypoxic environments and will use metabolic pathways that involve increased conversion of glucose to pyruvate and lactate, and a concomitant decrease in mitochondrial metabolism and mitochondrial mass. The molecular pathways responsible for inducing glycolysis are now being explored. These pathways seem to mediate multiple metabolic functions in cancer stem-like cells, leading to a highly migratory and angiogenesis-independent phenotype. Future challenges will be to identify and validate molecular targets involved in anaerobic metabolic pathways active in cancer stem-like cells and to determine how these pathways differ from regulatory pathways involved in normal stem cell function.

  • 6.
    Björkblom, Benny
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tabatabaei, Pedram
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Bergström, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Asklund, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma2020In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 122, no 2, p. 221-232Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses.

    METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects.

    RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment.

    CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.

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  • 7. Bosse, Yohan
    et al.
    Li, Zhonglin
    Xia, Jun
    Manem, Venkata
    Carreras-Torres, Robert
    Gabriel, Aurelie
    Gaudreault, Nathalie
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline
    Arnold, Susanne
    Bickeboeller, Heike
    Bojesen, Stig E.
    Brennan, Paul
    Brunnstrom, Hans
    Caporaso, Neil
    Chen, Chu
    Christiani, David C.
    Field, John K.
    Goodman, Gary
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Houlston, Richard
    Johansson, Mattias
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kiemeney, Lambertus A.
    Lam, Stephen
    Landi, Maria T.
    Lazarus, Philip
    Le Marchand, Loic
    Liu, Geoffrey
    Melander, Olle
    Rennert, Gadi
    Risch, Angela
    Rosenberg, Susan M.
    Schabath, Matthew B.
    Shete, Sanjay
    Song, Zhuoyi
    Stevens, Victoria L.
    Tardon, Adonina
    Wichmann, H-Erich
    Woll, Penella
    Zienolddiny, Shan
    Obeidat, Ma'en
    Timens, Wim
    Hung, Rayjean J.
    Joubert, Philippe
    Amos, Christopher I.
    McKay, James D.
    Transcriptome-wide association study reveals candidate causal genes for lung cancer2020In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 7, p. 1862-1878Article in journal (Refereed)
    Abstract [en]

    We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome‐wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never‐ and ever‐smokers). We performed replication analysis using lung data from the Genotype‐Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever‐smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3‐adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.

  • 8. Brenner, Darren R.
    et al.
    Fanidi, Anouar
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Muller, David C.
    Brennan, Paul
    Manjer, Jonas
    Byrnes, Graham
    Hodge, Allison
    Severi, Gianluca
    Giles, Graham G.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Johansson, Mattias
    Inflammatory Cytokines and Lung Cancer Risk in 3 Prospective Studies2017In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 185, no 2, p. 86-95Article in journal (Refereed)
    Abstract [en]

    To further investigate the role of inflammation in lung carcinogenesis, we evaluated associations between proinflammatory cytokines and lung cancer risk. We conducted a case-control study nested within 3 prospective cohort studies-the Melbourne Collaborative Cohort Study (1990-1994), the Malm Diet and Cancer Study (1991-1996), and the Northern Sweden Health and Disease Study (initiated in 1985)-involving 807 incident lung cancer cases and 807 smoking-matched controls. Conditional logistic regression models adjusting for serum cotinine concentrations were used to estimate odds ratios for lung cancer risk associated with concentrations of interleukin (IL)-1 beta, IL-2, IL-6, IL-8, IL-10, IL-12, interferon., tumor necrosis factor a, and granulocyte-macrophage colony-stimulating factor. We observed a higher lung cancer risk for participants with elevated concentrations of IL-6 and IL-8. These associations seemed to be stronger among former smokers (for fourth quartile vs. first quartile, odds ratio (OR) = 2.70, 95% confidence interval (CI): 1.55, 4.70) and current smokers (OR = 1.99, 95% CI: 1.15, 3.44) for IL-6 and among former smokers (OR = 2.83, 95% CI: 1.18, 6.75) and current smokers (OR = 1.30, 95% CI: 0.69, 2.44) for IL-8. No notable associations were observed among never smokers. Risk associations with IL-6 and IL-8 were observed for blood samples taken close to diagnosis (< 5 years) as well as more than 15 years postdiagnosis.

  • 9.
    Byun, Jinyoung
    et al.
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Han, Younghun
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Li, Yafang
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Xia, Jun
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States.
    Long, Erping
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Choi, Jiyeon
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Xiao, Xiangjun
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States.
    Zhu, Meng
    Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
    Zhou, Wen
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States.
    Sun, Ryan
    Department of Biostatistics, University of Texas, M.D. Anderson Cancer Center, TX, Houston, United States.
    Bossé, Yohan
    Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Department of Molecular Medicine, Laval University, QC, Quebec City, Canada.
    Song, Zhuoyi
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States.
    Schwartz, Ann
    Department of Oncology, Wayne State University School of Medicine, MI, Detroit, United States; Karmanos Cancer Institute, MI, Detroit, United States.
    Lusk, Christine
    Department of Oncology, Wayne State University School of Medicine, MI, Detroit, United States; Karmanos Cancer Institute, MI, Detroit, United States.
    Rafnar, Thorunn
    deCODE genetics/Amgen Sturlugata 8, Reykjavik, Iceland.
    Stefansson, Kari
    deCODE genetics/Amgen Sturlugata 8, Reykjavik, Iceland.
    Zhang, Tongwu
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Zhao, Wei
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Pettit, Rowland W.
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States.
    Liu, Yanhong
    Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Li, Xihao
    Department of Biostatistics, Harvard TH Chan School of Public Health, MA, Boston, United States.
    Zhou, Hufeng
    Department of Biostatistics, Harvard TH Chan School of Public Health, MA, Boston, United States.
    Walsh, Kyle M.
    Duke Cancer Institute, Duke University Medical Center, NC, Durham, United States.
    Gorlov, Ivan
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Gorlova, Olga
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Zhu, Dakai
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Rosenberg, Susan M.
    Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States.
    Pinney, Susan
    University of Cincinnati College of Medicine, OH, Cincinnati, United States.
    Bailey-Wilson, Joan E.
    National Human Genome Research Institute, NIH, MD, Baltimore, United States.
    Mandal, Diptasri
    Louisiana State University Health Sciences Center, LA, New Orleans, United States.
    de Andrade, Mariza
    Mayo Clinic, College of Medicine, MN, Rochester, United States.
    Gaba, Colette
    The University of Toledo College of Medicine and Life Sciences, University of Toledo, OH, Toledo, United States.
    Willey, James C.
    The University of Toledo College of Medicine and Life Sciences, University of Toledo, OH, Toledo, United States.
    You, Ming
    Center for Cancer Prevention, Houston Methodist Research Institute, TX, Houston, United States.
    Anderson, Marshall
    University of Cincinnati College of Medicine, OH, Cincinnati, United States.
    Wiencke, John K.
    Department of Neurological Surgery, University of California, San Francisco, CA, San Francisco, United States.
    Albanes, Demetrius
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Lam, Stephan
    Department of Integrative Oncology, BC Cancer, BC, Vancouver, Canada.
    Tardon, Adonina
    Public Health Department, University of Oviedo, ISPA and CIBERESP, Asturias, Spain.
    Chen, Chu
    Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Goodman, Gary
    Swedish Cancer Institute, WA, Seattle, United States.
    Bojeson, Stig
    Department of Clinical Biochemistry, Herlev Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Brenner, Hermann
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Landi, Maria Teresa
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Chanock, Stephen J.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Muley, Thomas
    Division of Cancer Epigenomics, DKFZ – German Cancer Research Center, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany.
    Risch, Angela
    Division of Cancer Epigenomics, DKFZ – German Cancer Research Center, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany; Department of Biosciences and Medical Biology, Allergy-Cancer-BioNano Research Centre, University of Salzburg, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria.
    Wichmann, H.-Erich
    Institute of Epidemiology, Helmholtz Center, Munich, Germany.
    Bickeböller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
    Christiani, David C.
    Department of Epidemiology, Harvard T.H.Chan School of Public Health, MA, Boston, United States.
    Rennert, Gad
    Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    Arnold, Susanne
    University of Kentucky, Markey Cancer Center, KY, Lexington, United States.
    Field, John K.
    Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay
    Department of Biostatistics, University of Texas, M.D. Anderson Cancer Center, TX, Houston, United States; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, TX, Houston, United States.
    Le Marchand, Loic
    Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States.
    Melander, Olle
    Faculty of Medicine, Lund University, Lund, Sweden.
    Brunnstrom, Hans
    Faculty of Medicine, Lund University, Lund, Sweden.
    Liu, Geoffrey
    University Health Network- The Princess Margaret Cancer Centre, Ontario, Toronto, Canada.
    Andrew, Angeline S.
    Departments of Epidemiology and Community and Family Medicine, Dartmouth College, NH, Hanover, United States.
    Kiemeney, Lambertus A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Shen, Hongbing
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Zienolddiny, Shanbeh
    National Institute of Occupational Health, Oslo, Norway.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Caporaso, Neil
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Cox, Angela
    Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
    Hong, Yun-Chul
    Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    Yuan, Jian-Min
    UPMC Hillman Cancer Center and Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, Pittsburgh, United States.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, WA, Spokane, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, FL, Tampa, United States.
    Aldrich, Melinda C.
    Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Patel, Alpa
    American Cancer Society, GA, Atlanta, United States.
    Lan, Qing
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Rothman, Nathaniel
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Taylor, Fiona
    Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
    Kachuri, Linda
    Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, San Francisco, United States.
    Witte, John S.
    Department of Epidemiology and Population Health, Stanford University, CA, Stanford, United States.
    Sakoda, Lori C.
    Division of Research, Kaiser Permanente Northern California, CA, Oakland, United States.
    Spitz, Margaret
    Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Brennan, Paul
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Lin, Xihong
    Department of Biostatistics, Harvard TH Chan School of Public Health, MA, Boston, United States.
    McKay, James
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Hung, Rayjean J.
    Lunenfeld-Tanenbaum Research Institute, Sinai Health System, ON, Toronto, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, ON, Toronto, Canada.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer2022In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 54, no 8, p. 1167-1177Article in journal (Refereed)
    Abstract [en]

    To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

  • 10. Carreras-Torres, Robert
    et al.
    Johansson, Mattias
    Haycock, Philip C.
    Wade, Kaitlin H.
    Relton, Caroline L.
    Martin, Richard M.
    Smith, George Davey
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline
    Arnold, Susanne M.
    Bickeböller, Heike
    Bojesen, Stig E.
    Brunnström, Hans
    Manjer, Jonas
    Brüske, Irene
    Caporaso, Neil E.
    Chen, Chu
    Christiani, David C.
    Christian, W. Jay
    Doherty, Jennifer A.
    Duell, Eric J.
    Field, John K.
    Davies, Michael P. A.
    Marcus, Michael W.
    Goodman, Gary E.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Haugen, Aage
    Hong, Yun-Chul
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Kraft, Peter
    Johansson, Mikael B.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lam, Stephen
    Landi, Maria Teresa
    Lazarus, Philip
    Le Marchand, Loïc
    Liu, Geoffrey
    Melander, Olle
    Park, Sungshim L.
    Rennert, Gad
    Risch, Angela
    Haura, Eric B.
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Savić, Milan
    Lissowska, Jolanta
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Mates, Dana
    Schabath, Matthew B.
    Shen, Hongbing
    Tardon, Adonina
    Teare, Dawn
    Woll, Penella
    Tsao, Ming-Sound
    Wu, Xifeng
    Yuan, Jian-Min
    Hung, Rayjean J.
    Amos, Christopher I.
    McKay, James
    Brennan, Paul
    Obesity, metabolic factors and risk of different histological types of lung cancer: a Mendelian randomization study2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 6, article id e0177875Article in journal (Refereed)
    Abstract [en]

    Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95% CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m(2)]), but not for adenocarcinoma (OR [95% CI] = 0.93 [0.79-1.08]) (P-heterogeneity = 4.3x10(-3)). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10(-3)), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95% CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95% CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

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  • 11.
    Cheng, Chao
    et al.
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Hong, Wei
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States.
    Li, Yafang
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Xiao, Xiangjun
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States.
    McKay, James
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Han, Younghun
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Byun, Jinyoung
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Peng, Bo
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Albanes, Demetrios
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda, United States.
    Lam, Stephen
    Department of Integrative Oncology, University of British Columbia, BC, Vancouver, Canada.
    Tardon, Adonina
    Public Health Department, University of Oviedo, ISPA and CIBERESP, Asturias, Spain.
    Chen, Chu
    Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States.
    Bojesen, Stig E.
    Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Landi, Maria T.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda, United States.
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Risch, Angela
    Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
    Bickeböller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
    Wichmann, H-Erich
    Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany.
    Christiani, David C.
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, Massachusetts, Boston, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Massachusetts, Boston, United States.
    Rennert, Gad
    Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    Arnold, Susanne
    University of Kentucky, Markey Cancer Center, Kentucky, Lexington, United States.
    Goodman, Gary
    Swedish Cancer Institute, WA, Seattle, United States.
    Field, John K.
    Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Davies, Michael P.A.
    Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay S.
    Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Texas, Houston, United States; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Texas, Houston, United States.
    Le Marchand, Loic
    Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States.
    Liu, Geoffrey
    University Health Network- The Princess Margaret Cancer Centre, California, Toronto, United States.
    Hung, Rayjean J.
    Luenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
    Andrew, Angeline S.
    Department of Epidemiology, Dartmouth College, New Hampshire, Hanover, United States; Department of Community and Family Medicine, Dartmouth College, New Hampshire, Hanover, United States.
    Kiemeney, Lambertus A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Zhu, Meng
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Shen, Hongbing
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Zienolddiny, Shan
    National Institute of Occupational Health, Oslo, Norway.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Cox, Angela
    Academic Unit of Clinical Oncology University of Sheffield, Weston Park Hospital, Whitham Road, Sheffield, United Kingdom.
    Hong, Yun-Chul
    Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    Yuan, Jian-Min
    University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, PA, Pittsburgh, United States.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, WA, Spokane, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Florida, Tampa, United States.
    Aldrich, Melinda C.
    Department of Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Brennan, Paul
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Li, Yong
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Gorlova, Olga
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Gorlov, Ivan
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Mosaic chromosomal alterations are associated with increased lung cancer risk: insight from the INTEGRAL-ILCCO cohort analysis2023In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380Article in journal (Refereed)
    Abstract [en]

    Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.

  • 12. Chuang, Shu-Chun
    et al.
    Fanidi, Anouar
    Ueland, Per Magne
    Relton, Caroline
    Midttun, Oivind
    Vollset, Stein Emil
    Gunter, Marc J.
    Seckl, Michael J.
    Travis, Ruth C.
    Wareham, Nicholas
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H. M.
    Bueno-de-Mesquita, H. Bas
    Boeing, Heiner
    Wientzek, Angelika
    Kuehn, Tilman
    Kaaks, Rudolf
    Tumino, Rosario
    Agnoli, Claudia
    Palli, Domenico
    Naccarati, Alessio
    Ardanaz Aicua, Eva
    Sanchez, Maria-Jose
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Agudo, Antonio
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Weiderpass, Elisabete
    Riboli, Elio
    Brennan, Paul J.
    Vineis, Paolo
    Johansson, Mattias
    Circulating Biomarkers of Tryptophan and the Kynurenine Pathway and Lung Cancer Risk2014In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 23, no 3, p. 461-468Article in journal (Refereed)
    Abstract [en]

    Background: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer. Methods: We conducted a nested case-control study within the European Prospective Investigation into Cancer andNutrition (EPIC) that included 893 incident lung cancer cases and 1,748matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk. Results: Tryptophan (P-trend = 2 Chi 10(-5)) and the kynurenine/ tryptophan ratio (KTR; P-trend 4 Chi 10(-5)) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th (vs. 1st)) were 0.52 [ 95% confidence interval (CI), 0.37-0.74] for tryptophan and 1.74 (95% CI, 1.24-2.45) for KTR. After adjusting for plasma methionine (available fromprevious work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted P-trend 0.13) and KTR (P-trend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62-4.94, P-trend -3 Chi 10(-5)) that was only marginally affected by adjusting for methionine. Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology. Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk.

  • 13.
    Dagnino, Sonia
    et al.
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Bodinier, Barbara
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Guida, Florence
    International Agency for Research on Cancer (IARC), Lyon, France.
    Smith-Byrne, Karl
    International Agency for Research on Cancer (IARC), Lyon, France.
    Petrovic, Dusan
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Epidemiology and Health Systems (DESS), University Center for General Medicine and Public Health (UNISANTE), Lausanne, Switzerland; Department and Division of Primary Care Medicine, University Hospital of Geneva, Geneva, Switzerland.
    Whitaker, Matthew D.
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Nøst, Therese Haugdahl
    Department of Community Medicine, UiT- The Arctic University of Norway, Tromsø, Norway.
    Agnoli, Claudia
    Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Palli, Domenico
    Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
    Sacerdote, Carlotta
    Unit of Cancer Epidemiology, Citta della Salute e della Scienza University-Hospital, Turin, Italy.
    Panico, Salvatore
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Tumino, Rosario
    Cancer Registry and Histopathology Department, Provincial Health Authority (ASP) Ragusa, Italy.
    Schulze, Matthias B.
    Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Keski-Rahkonen, Pekka
    International Agency for Research on Cancer (IARC), Lyon, France.
    Scalbert, Augustin
    International Agency for Research on Cancer (IARC), Lyon, France.
    Vineis, Paolo
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Italian Institute of Technology, Genova, Italy.
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Sandanger, Torkjel M.
    Department of Community Medicine, UiT- The Arctic University of Norway, Tromsø, Norway.
    Vermeulen, Roel C.H.
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands.
    Chadeau-Hyam, Marc
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands.
    Prospective identification of elevated circulating CDCP1 in patients years before onset of lung cancer2021In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, no 13, p. 3738-3748Article in journal (Refereed)
    Abstract [en]

    Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis.

  • 14. Dai, Juncheng
    et al.
    Huang, Mingtao
    Amos, Christopher I.
    Hung, Rayjean J.
    Tardon, Adonina
    Andrew, Angeline
    Chen, Chu
    Christiani, David C.
    Albanes, Demetrius
    Rennert, Gadi
    Fan, Jingyi
    Goodman, Gary
    Liu, Geoffrey
    Field, John K.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kiemeney, Lambertus A.
    Le Marchand, Loic
    Schabath, Matthew B.
    Johansson, Mattias
    Aldrich, Melinda C.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Caporaso, Neil
    Lazarus, Philip
    Lam, Stephan
    Bojesen, Stig E.
    Arnold, Susanne
    Landi, Maria Teresa
    Risch, Angela
    Wichmann, H-Erich
    Bickeboller, Heike
    Brennan, Paul
    Shete, Sanjay
    Melander, Olle
    Brunnstrom, Hans
    Zienolddiny, Shan
    Woll, Penella
    Stevens, Victoria
    Hu, Zhibin
    Shen, Hongbing
    Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk2020In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 10, p. 2855-2864Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung ncer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant netic polymorphisms in the human genome. INDELs are highly associated with multiple human seases, including lung cancer. However, limited studies with large-scale samples have been available to stematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta- alysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional notations were performed to further explore the potential function of lung cancer risk INDELs. nditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci re identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 x 10(- ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 x 10(-7); 12p13.31: rs71450133, Deletion, OR = 09, p = 8.83 x 10(-7); and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 x 10(-8)). The eQTL alysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by gulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, e INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be tentially functional genetic variants for lung cancer risk. Further functional experiments are needed to tter understand INDEL mechanisms in carcinogenesis.

  • 15. Dai, Juncheng
    et al.
    Li, Zhihua
    Amos, Christopher I.
    Hung, Rayjean J.
    Tardon, Adonina
    Andrew, Angeline S.
    Chen, Chu
    Christiani, David C.
    Albanes, Demetrios
    van der Heijden, Erik H. F. M.
    Duell, Eric J.
    Rennert, Gad
    Mckay, James D.
    Yuan, Jian-Min
    Field, John K.
    Manjer, Jonas
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Le Marchand, Loic
    Teare, M. Dawn
    Schabath, Matthew B.
    Aldrich, Melinda C.
    Tsao, Ming-Sound
    Lazarus, Philip
    Lam, Stephen
    Bojesen, Stig E.
    Arnold, Susanne
    Wu, Xifeng
    Haugen, Aage
    Janout, Vladimir
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brhane, Yonathan
    Fernandez-Somoano, Ana
    Kiemeney, Lambertus A.
    Davies, Michael P. A.
    Zienolddiny, Shanbeh
    Hu, Zhibin
    Shen, Hongbing
    Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci2019In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 40, no 3, p. 432-440Article in journal (Refereed)
    Abstract [en]

    DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 x 10(-7)) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 x 10(-6)) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 x 10(-4)). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.

  • 16.
    de Jager, Vincent D.
    et al.
    Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Timens, Wim
    Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Bayle, Arnaud
    Oncostat U1018, Inserm, Paris-Saclay University, Gustave Roussy, Villejuif, France.
    Botling, Johan
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy of University of Gothenburg, Gothenburg, Sweden.
    Brcic, Luka
    Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
    Büttner, Reinhard
    Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
    Fernandes, Maria Gabriela O.
    Pulmonology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.
    Havel, Libor
    Charles University and Thomayer Hospital, Prague, Czech Republic.
    Hochmair, Maximilian J.
    Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria; Department of Respiratory and Critical Care Medicine, Klinik Floridsdorf, Vienna Healthcare Group, Vienna, Austria.
    Hofman, Paul
    IHU RespirERA, FHU OncoAge, Nice University Hospital, Côte d'Azur University, Nice, France.
    Janssens, Annelies
    Department of Oncology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Kempen, Léon
    Department of Pathology, University Hospital Antwerp, University of Antwerp, Edegem, Belgium.
    Kern, Izidor
    Laboratory for Cytology and Pathology, University Clinic Golnik, Golnik, Slovenia.
    Lopez-Rios, Fernando
    Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Research Institute Hospital 12 de Octubre (i+12), Ciberonc, Madrid, Spain.
    Lüchtenborg, Margreet
    National Disease Registration Service, NHS England, London, United Kingdom; Centre for Cancer, Society & Public Health, King's College London, London, United Kingdom.
    Machado, José Carlos
    Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculty of Medicine of the University of Porto, Institute for Research and Innovation in Health (i3S), Porto, Portugal.
    Mohorcic, Katja
    University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
    Paz-Ares, Luis
    Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, H12O-CNIO Lung Cancer Clinical Research Unit, Research Institute Hospital 12 de Octubre (i+12)/Spanish National Cancer Research Center (CNIO), Ciberonc, Madrid, Spain.
    Popat, Sanjay
    Lung Unit, Royal Marsden NHS Trust, London, United Kingdom.
    Ryška, Aleš
    The Fingerland Department of Pathology, Charles University Medical Faculty and University Hospital, Czech Republic.
    Taniere, Phillipe
    Department of Histopathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
    Wolf, Jürgen
    Lung Cancer Group Cologne, Department I for Internal Medicine and Center for Integrated Oncology Cologne/Bonn, University Hospital Cologne, Cologne, Germany.
    Schuuring, Ed
    Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    van der Wekken, Anthonie J.
    Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
    Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries2024In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 38, article id 100838Article, review/survey (Refereed)
    Abstract [en]

    In the past two decades, the treatment of metastatic non-small cell lung cancer (NSCLC), has undergone significant changes due to the introduction of targeted therapies and immunotherapy. These advancements have led to the need for predictive molecular tests to identify patients eligible for targeted therapy. This review provides an overview of the development and current application of targeted therapies and predictive biomarker testing in European patients with advanced stage NSCLC. Using data from eleven European countries, we conclude that recommendations for predictive testing are incorporated in national guidelines across Europe, although there are differences in their comprehensiveness. Moreover, the availability of recently EMA-approved targeted therapies varies between European countries. Unfortunately, routine assessment of national/regional molecular testing rates is limited. As a result, it remains uncertain which proportion of patients with metastatic NSCLC in Europe receive adequate predictive biomarker testing. Lastly, Molecular Tumor Boards (MTBs) for discussion of molecular test results are widely implemented, but national guidelines for their composition and functioning are lacking. The establishment of MTB guidelines can provide a framework for interpreting rare or complex mutations, facilitating appropriate treatment decision-making, and ensuring quality control.

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  • 17. Dewi, Nikmah Utami
    et al.
    Boshuizen, Hendriek C.
    Johansson, Mattias
    Vineis, Paolo
    Kampman, Ellen
    Steffen, Annika
    Tjonneland, Anne
    Halkjaer, Jytte
    Overvad, Kim
    Severi, Gianluca
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Li, Kuanrong
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Klinaki, Eleni
    Tumino, Rosario
    Palli, Domenico
    Mattiello, Amalia
    Tagliabue, Giovanna
    Peeters, Petra H.
    Vermeulen, Roel
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Maria Huerta, Jose
    Agudo, Antonio
    Sanchez, Maria-Jose
    Ardanaz, Eva
    Dorronsoro, Miren
    Ramon Quiros, Jose
    Sonestedt, Emily
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Key, Tim
    Khaw, Kay-Tee
    Wareham, Nick
    Cross, Amanda J.
    Norat, Teresa
    Riboli, Elio
    Fanidi, Anouar
    Muller, David
    Bueno-de-Mesquita, H. Bas
    Anthropometry and the Risk of Lung Cancer in EPIC2016In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 184, no 2, p. 129-139Article in journal (Refereed)
    Abstract [en]

    The associations of body mass index (BMI) and other anthropometric measurements with lung cancer were examined in 348,108 participants in the European Investigation Into Cancer and Nutrition (EPIC) between 1992 and 2010. The study population included 2,400 case patients with incident lung cancer, and the average length of follow-up was 11 years. Hazard ratios were calculated using Cox proportional hazard models in which we modeled smoking variables with cubic splines. Overall, there was a significant inverse association between BMI (weight (kg)/height (m)(2)) and the risk of lung cancer after adjustment for smoking and other confounders (for BMI of 30.0-34.9 versus 18.5-25.0, hazard ratio = 0.72, 95% confidence interval: 0.62, 0.84). The strength of the association declined with increasing follow-up time. Conversely, after adjustment for BMI, waist circumference and waist-to-height ratio were significantly positively associated with lung cancer risk (for the highest category of waist circumference vs. the lowest, hazard ratio = 1.25, 95% confidence interval: 1.05, 1.50). Given the decline of the inverse association between BMI and lung cancer over time, the association is likely at least partly due to weight loss resulting from preclinical lung cancer that was present at baseline. Residual confounding by smoking could also have influenced our findings.

  • 18.
    Du, Mulong
    et al.
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Xin, Junyi
    Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Jiangsu, Nanjing, China.
    Zheng, Rui
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Yuan, Qianyu
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Wang, Zhihui
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Liu, Hongliang
    Duke Cancer Institute, Duke University Medical Center, NC, Durham, United States; Department of Population Health Sciences, Duke University School of Medicine, NC, Durham, United States.
    Liu, Hanting
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Cai, Guoshuai
    Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, SC, Columbia, United States.
    Albanes, Demetrius
    Division of Cancer Epidemiology and Genetics, NCI, US NIH, MD, Bethesda, United States.
    Lam, Stephen
    British Columbia Cancer Agency, BC, Vancouver, Canada.
    Tardon, Adonina
    Faculty of Medicine, University of Oviedo, ISPA and CIBERESP, Oviedo, Spain.
    Chen, Chu
    Program in Epidemiology, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Bojesen, Stig E.
    Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.
    Landi, Maria Teresa
    Division of Cancer-Epidemiology and Genetics, NCI, US NIH, MD, Bethesda, United States.
    Johansson, Mattias
    International Agency for Research on Cancer, World-Health Organization, Lyon, France.
    Risch, Angela
    University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; German Center for Lung Research (DZL), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Bickeboller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg August University Gottingen, Gottingen, Germany.
    Wichmann, H-Erich
    Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilian University, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany.
    Rennert, Gad
    Clalit National Cancer Control Center, Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel.
    Arnold, Susanne
    Markey Cancer Center, University of Kentucky, KY, Lexington, United States.
    Brennan, Paul
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Field, John K.
    Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay S.
    Department of Epidemiology, Division of Cancer Prevention and Population Science, The University of Texas, MD Anderson Cancer Center, TX, Houston, United States.
    Le Marchand, Loïc
    Epidemiology Program, University of Hawaii Cancer Center, Hawaii, Honolulu, United States.
    Liu, Geoffrey
    Princess Margaret Cancer Center, University of Toronto, ON, Toronto, Canada.
    Andrew, Angeline S.
    Norris Cotton Cancer Center, Geisel School of Medicine, NH, Hanover, United States.
    Kiemeney, Lambertus A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Zienolddiny, Shan
    National Institute of Occupational Health, Oslo, Norway.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Department of Radiation Sciences, Umeå, Sweden.
    Caporaso, Neil E.
    Division of Cancer Epidemiology and Genetics, NCI, US-NIH, MD, Bethesda, United States.
    Cox, Angela
    Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
    Hong, Yun-Chul
    Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    Yuan, Jian-Min
    UPMC Hillman Cancer Center, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, Pittsburgh, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, FL, Tampa, United States.
    Aldrich, Melinda C.
    Department of Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Wang, Meilin
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Shen, Hongbing
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Chen, Feng
    Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Zhang, Zhengdong
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Hung, Rayjean J.
    Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, University of Toronto, ON, Toronto, Canada.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor Medical College, TX, Houston, United States.
    Wei, Qingyi
    Duke Cancer Institute, Duke University Medical Center, NC, Durham, United States; Department of Population Health Sciences, Duke University School of Medicine, NC, Durham, United States.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, WA, Spokane, United States.
    Christiani, David C.
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Department of Medicine, Massachusetts General Hospital, MA, Boston, United States.
    Cyp2a6 activity and cigarette consumption interact in smoking-related lung cancer susceptibility2024In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 84, no 4, p. 616-625Article in journal (Refereed)
    Abstract [en]

    Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen–metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke–exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85–0.91, P = 2.18 X 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis.

  • 19.
    Eriksson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sandström, M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Treatment of Glioblastoma: Improvements over two decades at a single centre2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 236-236Article in journal (Other academic)
    Abstract [en]

    INTRODUCTION: Glioblastoma (GBM) is a rapidly progressing tumour with a short overall survival. The treatment of GBM has evolved over the last decades and is today multimodal including surgery with maximal tumour resection followed by radiotherapy and chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single centre.

    PATIENTS AND METHODS: 244 patients treated for GBM 2005 - 2015 has been included in a tissue bank with tumour tissue and/or blood samples. A clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment. Survival was also studied for all 571 patients in our region diagnosed with GBM between 1995 and 2015.

    RESULTS: The overall median survival for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995–1996 and 2010–2015, respectively (p<0.05). The two-year survival for the same time periods improved from 7.4% to 17.8% (p<0.01). After the introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased survival was noted. The implementation of intraoperative 5-aminolevulinic acid did, in patients that underwent tumour resection, increase the number of total tumour resections (≥95%) from 32.6% to 54.1% (p<0.001). Positive prognostic factors were young age, good performance status, absence of diabetes or metabolic disease, total tumour resection and completion of postoperative radiochemotherapy.

    CONCLUSIONS: The results of this study are in line with earlier results regarding survival and prognostic factors. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.

  • 20.
    Eriksson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kahari, Jenna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vestman, Amanda
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Mattias
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Sandström, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Improved treatment of glioblastoma: changes in survival over two decades at a single regional Centre2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 3, p. 334-341Article in journal (Refereed)
    Abstract [en]

    Background: Glioblastoma (GBM) is an aggressive brain tumor with a short overall survival (OS) in general. The treatment of GBM has evolved over the last decades and is today multimodal including surgical resection followed by radiochemotherapy and adjuvant chemotherapy for patients in good performance status. The aim of this study was to evaluate the development of treatment and the outcome for GBM patients at a single regional center.

    Patients and methods: Survival was studied for 571 patients in our region diagnosed with GBM between 1995 and 2015. Samples from 244 patients out of those treated 2005-2015 have been included in a tissue/blood bank and a clinical database has been set up with basic patient characteristics and details on surgery and non-surgical treatment.

    Results: The median OS for all patients from 1995 to 2015 was 9.3 months. There was a stepwise improvement from 6.9 to 10.3 months for patients diagnosed 1995-1996 and 2010-2015, respectively (p<.05). The 2-year survival for the same time periods improved from 7% to 18% (p<.01). After introduction of postoperative radiochemotherapy for patients in good performance status in 2005 an increased OS was noted and following implementation of intraoperative 5-aminolevulinic acid the number of tumor resection 95% did increase from 33% to 54% (p<.001). Positive prognostic factors for survival were young age, good performance status, absence of inflammatory disease, absence of diabetes or metabolic disease, tumor resection 95%, and completion of postoperative radiochemotherapy.

    Discussion: The results of this study are consistent with earlier results regarding survival and prognostic factors and confirm results from randomized controlled trials in a clinical setting. Despite the improvements made, the prognosis is still dismal and the need for further research on GBM treatment is great.

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  • 21.
    Fallah, Mahsa
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yue
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Brodén, Jessica
    Bäckman, Assar
    Lundskog, Bertil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Blomqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Liu, Kui
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen activation is required for the development of radiation-induced dermatitis2018In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 9, no 11, article id 1051Article in journal (Refereed)
    Abstract [en]

    Skin damage caused by radiation therapy (radiodermatitis) is a severe side effect of radiotherapy in cancer patients, and there is currently a lack of effective strategies to prevent or treat such skin damage. In this work, we show with several lines of evidence that plasminogen, a pro-inflammatory factor, is key for the development of radiodermatitis. After skin irradiation in wild type (plg+/+) mice, the plasminogen level increased in the radiated area, leading to severe skin damage such as ulcer formation. However, plasminogen-deficient (plg−/−) mice and mice lacking plasminogen activators were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreased radiodermatitis in plg+/+ mice and prevented radiodermatitis in plg+/ mice. Together with studies at the molecular level, we report that plasmin is required for the induction of inflammation after irradiation that leads to radiodermatitis, and we propose that inhibition of plasminogen activation can be a novel treatment strategy to reduce and prevent the occurrence of radiodermatitis in patients.

     

     

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  • 22.
    Fallah, Mahsa
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Viklund, Emil
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bäckman, Assar
    Brodén, Jessica
    Lundskog, Bertil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Blomqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Omnio AB, Umeå, Sweden.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds2020In: Cell Death and Disease, E-ISSN 2041-4889, Vol. 11, no 3Article in journal (Refereed)
    Abstract [en]

    Around 95% of cancer patients undergoing radiotherapy experience cutaneous side effects, and some develop radiation wounds or fibrosis. Currently, there is no effective treatment for these indications. We show here that plasminogen administration enhanced the healing of radiation wounds via pleiotropic effects on gene expression. Using RNA sequencing, we found that plasminogen downregulated the expression of genes in the TLR, TNF, WNT, MAPK, and TGF-β signaling pathways, and enhanced the anti-inflammatory effect of arachidonic acid, leading to significantly decreased inflammation and improved remodeling of granulation tissue compared with placebo treatment. In addition, plasminogen induced metabolic changes, including decreased glycolysis. Importantly, many of the factors downregulated by plasminogen are pro-fibrotic. Therefore, in radiation wounds with excessive inflammation, plasminogen is able to enhance and redirect the healing process, such that it more closely resembles physiological healing with significantly reduced risk for developing fibrosis. This makes plasminogen an attractive drug candidate for the treatment of radiation wounds in cancer patients.

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  • 23.
    Fallah, Mahsa
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Viklund, Emil
    Shen, Yue
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Bäckman, Assar
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundskog, Bertil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Blomqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wilczynska, Malgorzata
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ny, Tor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Plasminogen enhances the healing of radiation-induced wounds via decreased expression of pro-inflammatory and pro-fibrotic factorsManuscript (preprint) (Other academic)
  • 24. Fanidi, Anouar
    et al.
    Carreras-Torres, Robert
    Larose, Tricia L.
    Yuan, Jian-Min
    Stevens, Victoria L.
    Weinstein, Stephanie J.
    Albanes, Demetrius
    Prentice, Ross
    Pettinger, Mary
    Cai, Qiuyin
    Blot, William J.
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    McCullough, Marjorie L.
    Le Marchand, Loic
    Wilkens, Lynne R.
    Haiman, Christopher A.
    Zhang, Xuehong
    Stampfer, Meir J.
    Smith-Warner, Stephanie A.
    Giovannucci, Edward
    Giles, Graham G.
    Hodge, Allison M.
    Severi, Gianluca
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Langhammer, Arnulf
    Brumpton, Ben M.
    Wang, Renwei
    Gao, Yu-Tang
    Ericson, Ulrika
    Bojesen, Stig E.
    Arnold, Susanne M.
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Li, Honglan
    Zheng, Wei
    Lan, Qing
    Visvanathan, Kala
    Hoffman-Bolton, Judith
    Ueland, Per M.
    Midttun, Oivind
    Caporaso, Neil E.
    Purdue, Mark
    Freedman, Neal D.
    Buring, Julie E.
    Lee, I-Min
    Sesso, Howard D.
    Gaziano, J. Michael
    Manjer, Jonas
    Relton, Caroline L.
    Hung, Rayjean J.
    Amos, Chris, I
    Johansson, Mattias
    Brennan, Paul
    Is high vitamin B12 status a cause of lung cancer?2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 6, p. 1499-1503Article in journal (Refereed)
    Abstract [en]

    Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case–control study, complemented with a Mendelian randomization (MR) approach in an independent case–control sample. We used pre‐diagnostic biomarker data from 5183 case–control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case–control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06–1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD] = 1.08, 95%CI = 1.00–1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

  • 25. Fanidi, Anouar
    et al.
    Muller, David C
    Yuan, Jian-Min
    Stevens, Victoria L
    Weinstein, Stephanie J
    Albanes, Demetrius
    Prentice, Ross
    Thomsen, Cynthia A
    Pettinger, Mary
    Cai, Qiuyin
    Blot, William J
    Wu, Jie
    Arslan, Alan A
    Zeleniuch-Jacquotte, Anne
    McCullough, Marjorie L
    Le Marchand, Loic
    Wilkens, Lynne R
    Haiman, Christopher A
    Zhang, Xuehong
    Han, Jiali
    Stampfer, Meir J
    Smith-Warner, Stephanie A
    Giovannucci, Edward
    Giles, Graham G
    Hodge, Allison M
    Severi, Gianluca
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Langhammer, Arnulf
    Krokstad, Steinar
    Næss, Marit
    Wang, Renwei
    Gao, Yu-Tang
    Butler, Lesley M
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Li, Honglan
    Zheng, Wei
    Lan, Qing
    Visvanathan, Kala
    Bolton, Judith Hoffman
    Ueland, Per Magne
    Midttun, Øivind
    Ulvik, Arve
    Caporaso, Neil E
    Purdue, Mark
    Ziegler, Regina G
    Freedman, Neal D
    Buring, Julie E
    Lee, I-Min
    Sesso, Howard D
    Gaziano, J Michael
    Manjer, Jonas
    Ericson, Ulrika
    Relton, Caroline
    Brennan, Paul
    Johansson, Mattias
    Circulating Folate, Vitamin B6, and Methionine in Relation to Lung Cancer Risk in the Lung Cancer Cohort Consortium (LC3)2018In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 110, no 1, article id djx119Article in journal (Refereed)
    Abstract [en]

    Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.

    Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.

    Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.

    Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.

  • 26. Fanidi, Anouar
    et al.
    Relton, Caroline
    Ueland, Per Magne
    Midttun, Øivind
    Vollset, Stein Emil
    Travis, Ruth C.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Bueno-de-Mesquita, H. B(as)
    Ros, Martine
    Boeing, Heiner
    Tumino, Rosario
    Panico, Salvatore
    Palli, Domenico
    Sieri, Sabina
    Vineis, Paolo
    Sánchez, María-José
    Huerta, José María
    Barricarte Gurrea, Aurelio
    Luján-Barroso, Leila
    Quirós, J. Ramón
    Tjønneland, Anne
    Halkjær, Jytte
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Cadeau, Claire
    Weiderpass, Elisabete
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Riboli, Elio
    Brennan, Paul
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    A prospective study of one-carbon metabolism biomarkers and cancer of the head and neck and esophagus2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 4, p. 915-927Article in journal (Refereed)
    Abstract [en]

    Experimental and epidemiological data suggest that factors of one-carbon metabolism are important in the pathogenesis of several cancers, but prospective data on head and neck cancer (HNC) and esophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants from 10 countries who donated a blood sample. The current study included 516 cancer cases of the head and neck and esophagus and 516 individually matched controls. Plasma levels of vitamins B2, B6, B9 (folate), B12, and methionine and homocysteine were measured in pre-diagnostic plasma samples and analyzed in relation to HNC and esophagus cancer risk, as well as post-diagnosis all-cause mortality. After controlling for risk factors, study participants with higher levels of homocysteine had elevated risk of HNC, the odds ratio (OR) in conditional analysis when comparing the top and bottom quartiles of homocysteine [ORQ4vs. Q1] being 2.13 (95% confidence interval [95% CI] 1.13-4.00, p for trend 0.009). A slight decrease in HNC risk was also seen among subjects with higher levels of folate (ORQ4vs. Q1 0.63, 95% CI 0.35-1.16, p for trend 0.02). Subgroup analyses by anatomical sub-site indicated particularly strong associations with circulating homocysteine for oral cavity and gum cancer (p for trend 8 x 10(-4)), as well as for oropharynx cancer (p for trend 0.008). Plasma concentrations of the other investigated biomarkers did not display any clear association with risk or survival. In conclusion, study participants with elevated circulating levels of homocysteine had increased risk of developing squamous cell carcinoma of the head and neck. What's new? One-carbon metabolism (OCM) involves the transfer of a carbon unit from methyl donor nutrients to molecules involved in the synthesis and methylation of DNA. As a result, dietary imbalances or deficiencies in nutrients crucial for OCM may affect DNA replication, repair, and regulation, potentially facilitating cancer development. This analysis of circulating levels of OCM nutrients in head and neck cancer and esophageal cancer patients and matched controls reveals an association between elevated levels of the amino acid homocysteine and increased risk of squamous cell carcinoma of the head and neck. Risk was decreased slightly by elevated folate levels.

  • 27. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015In: Nature Communications, E-ISSN 2041-1723, Vol. 6, article id 10192Article in journal (Refereed)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

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  • 28.
    Feng, Xiaoshuang
    et al.
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Muller, David C.
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Epidemiology and Biostatistics, School of Public Health, MRC-PHE, Centre for Environment and Health, Imperial College London, London, United Kingdom.
    Zahed, Hana
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Alcala, Karine
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Guida, Florence
    Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Smith-Byrne, Karl
    Cancer Epidemiology Unit, Oxford Population Health, University of Oxford, Oxford, United Kingdom.
    Yuan, Jian-Min
    UPMC Hillman Cancer Centre, PA, Pittsburgh, United States; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, Pittsburgh, United States.
    Koh, Woon-Puay
    Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A∗STAR), Singapore.
    Wang, Renwei
    UPMC Hillman Cancer Centre, PA, Pittsburgh, United States.
    Milne, Roger L.
    Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Australia; School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia.
    Bassett, Julie K.
    Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia.
    Langhammer, Arnulf
    HUNT Research Center, Department of Public Health and Nursing, NTNU Norwegian University of Science and Technology, Levanger, Norway; Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
    Hveem, Kristian
    HUNT Research Center, Department of Public Health and Nursing, NTNU Norwegian University of Science and Technology, Levanger, Norway; Department of Public Health and Nursing, K.G. Jebsen Centre for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway.
    Stevens, Victoria L.
    Rollins School of Public Health, Emory University, GA, Atlanta, United States.
    Wang, Ying
    American Cancer Society, GA, Atlanta, United States.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tjønneland, Anne
    Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
    Tumino, Rosario
    Hyblean Association for Epidemiological Research, AIRE ONLUS Ragusa, Italy.
    Sheikh, Mahdi
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Johansson, Mattias
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Robbins, Hilary A.
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Evaluation of pre-diagnostic blood protein measurements for predicting survival after lung cancer diagnosis2023In: EBioMedicine, E-ISSN 2352-3964, Vol. 92, article id 104623Article in journal (Refereed)
    Abstract [en]

    Background: To evaluate whether circulating proteins are associated with survival after lung cancer diagnosis, and whether they can improve prediction of prognosis.

    Methods: We measured up to 1159 proteins in blood samples from 708 participants in 6 cohorts. Samples were collected within 3 years prior to lung cancer diagnosis. We used Cox proportional hazards models to identify proteins associated with overall mortality after lung cancer diagnosis. To evaluate model performance, we used a round-robin approach in which models were fit in 5 cohorts and evaluated in the 6th cohort. Specifically, we fit a model including 5 proteins and clinical parameters and compared its performance with clinical parameters only.

    Findings: There were 86 proteins nominally associated with mortality (p < 0.05), but only CDCP1 remained statistically significant after accounting for multiple testing (hazard ratio per standard deviation: 1.19, 95% CI: 1.10–1.30, unadjusted p = 0.00004). The external C-index for the protein-based model was 0.63 (95% CI: 0.61–0.66), compared with 0.62 (95% CI: 0.59–0.64) for the model with clinical parameters only. Inclusion of proteins did not provide a statistically significant improvement in discrimination (C-index difference: 0.015, 95% CI: −0.003 to 0.035).

    Interpretation: Blood proteins measured within 3 years prior to lung cancer diagnosis were not strongly associated with lung cancer survival, nor did they importantly improve prediction of prognosis beyond clinical information.

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  • 29.
    Feng, Xiaoshuang
    et al.
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Wu, Wendy Yi-Ying
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Onwuka, Justina Ucheojor
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Alcala, Karine
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Smith-Byrne, Karl
    Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
    Zahed, Hana
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Guida, Florence
    Environment and Lifestyle Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Wang, Renwei
    Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, PA, Pittsburgh, United States.
    Bassett, Julie K.
    Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
    Stevens, Victoria
    Rollins School of Public Health, Emory University, GA, Atlanta, United States.
    Wang, Ying
    American Cancer Society, GA, Atlanta, United States.
    Weinstein, Stephanie
    Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, Rockville, United States.
    Freedman, Neal D.
    Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, Rockville, United States.
    Chen, Chu
    Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, WA, Seattle, United States.
    Tinker, Lesley
    Women's Health Initiative Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Nøst, Therese Haugdahl
    Department of Community Medicine, University of Tromsø, Arctic University of Norway, Tromsø, Norway.
    Koh, Woon-Puay
    Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore.
    Muller, David
    Division of Genetic Medicine, Imperial College London School of Public Health, London, United Kingdom.
    Colorado-Yohar, Sandra M.
    Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
    Tumino, Rosario
    Hyblean Association for Epidemiological Research, Ragusa, Italy.
    Hung, Rayjean J.
    Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States.
    Lin, Xihong
    Department of Biostatistics, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, MA, Cambridge, United States; Department of Statistics, Harvard University, MA, Cambridge, United States.
    Zhang, Xuehong
    Brigham and Women's Hospital, Harvard Medical School, MA, Boston, United States.
    Arslan, Alan A.
    Department of Population Health, New York University School of Medicine, New York, NY, USA.
    Sánchez, Maria-Jose
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ib, Granada, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
    Sørgjerd, Elin Pettersen
    HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway.
    Severi, Gianluca
    Inserm, Université Paris-Saclay, Villejuif, France.
    Hveem, Kristian
    HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway.
    Brennan, Paul
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Langhammer, Arnulf
    HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway; Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
    Milne, Roger L.
    Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
    Yuan, Jian-Min
    Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, PA, Pittsburgh, United States; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, Pittsburgh, United States.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Robbins, Hilary A.
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Johansson, Mattias
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools2023In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 115, no 9, p. 1050-1059Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test.

    METHODS: We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided.

    RESULTS: The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference = .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model.

    CONCLUSION: Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung.

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  • 30. Ferreiro-Iglesias, Aida
    et al.
    Lesseur, Corina
    McKay, James
    Hung, Rayjean J.
    Han, Younghun
    Zong, Xuchen
    Christiani, David
    Johansson, Mattias
    Xiao, Xiangjun
    Li, Yafang
    Qian, David C.
    Ji, Xuemei
    Liu, Geoffrey
    Caporaso, Neil
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Kontic, Milica
    Ognjanovic, Simona
    Lissowska, Jolanta
    Szolkowska, Malgorzata
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Bolca, Ciprian
    Savic, Milan
    Ognjanovic, Miodrag
    Bojesen, Stig Egil
    Wu, Xifeng
    Albanes, Demetrios
    Aldrich, Melinda C.
    Tardon, Adonina
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    Le Marchand, Loic
    Rennert, Gadi
    Chen, Chu
    Doherty, Jennifer
    Goodman, Gary
    Bickeboeller, Heike
    Wichmann, H-Erich
    Risch, Angela
    Rosenberger, Albert
    Shen, Hongbing
    Dai, Juncheng
    Field, John K.
    Davies, Michael
    Woll, Penella
    Teare, M. Dawn
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Yuan, Jian-Min
    Hong, Yun-Chul
    Haugen, Aage
    Zienolddiny, Shanbeh
    Lam, Stephen
    Tsao, Ming-Sound
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Schabath, Matthew B.
    Andrew, Angeline
    Duell, Eric
    Melander, Olle
    Brunnstrom, Hans
    Lazarus, Philip
    Arnold, Susanne
    Slone, Stacey
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Landi, Maria Teresa
    Amos, Christopher, I
    Brennan, Paul
    Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 3927Article in journal (Refereed)
    Abstract [en]

    Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

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  • 31. Guida, Florence
    et al.
    Sun, Nan
    Bantis, Leonidas E.
    Muller, David C.
    Li, Peng
    Taguchi, Ayumu
    Dhillon, Dilsher
    Kundnani, Deepali L.
    Patel, Nikul J.
    Yan, Qingxiang
    Byrnes, Graham
    Moons, Karel G. M.
    Tjonneland, Anne
    Panico, Salvatore
    Agnoli, Claudia
    Vineis, Paolo
    Palli, Domenico
    Bueno-de-Mesquita, Bas
    Peeters, Petra H.
    Agudo, Antonio
    Huerta, Jose M.
    Dorronsoro, Miren
    Rodriguez Barranco, Miguel
    Ardanaz, Eva
    Travis, Ruth C.
    Byme, Karl Smith
    Boeing, Heiner
    Steffen, Annika
    Kaaks, Rudolf
    Huesing, Anika
    Trichopoulou, Antonia
    Lagiou, Pagona
    La Vecchia, Carlo
    Severi, Gianluca
    Boutron-Ruault, Marie-Christine
    Sandanger, Torkjel M.
    Weiderpass, Elisabete
    Nost, Therese H.
    Tsilidis, Kostas
    Riboli, Elio
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Goodman, Gary E.
    Feng, Ziding
    Brennan, Paul
    Johansson, Mattias
    Hanash, Samir M.
    Assessment of Lung Cancer Risk on the Basis of a Biomarker Panel of Circulating Proteins2018In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 4, no 10, article id e182078Article in journal (Refereed)
    Abstract [en]

    Importance  There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases.

    Objective  To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria.

    Design, Setting, and Participants  Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS).

    Main Outcomes and Measures  Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity).

    Results  In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model.

    Conclusions and Relevance  This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening.

  • 32. Hallqvist, Andreas
    et al.
    Bergström, Stefan
    Björkestrand, Hedvig
    Svärd, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ekman, Simon
    Lundin, Erik
    Holmberg, Erik
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Friesland, Signe
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nyman, Jan
    Dose escalation to 84 Gy with concurrent chemotherapy in stage III NSCLC appears excessively toxic: Results from a prematurely terminated randomized phase II trial2018In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 122, p. 180-186Article in journal (Refereed)
    Abstract [en]

    Objectives: Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease. To investigate whether radiation dose escalation based on individual normal tissue constraints can improve outcome, the Swedish lung cancer study group launched this randomized phase II trial.

    Materials and Methods: NSCLC patients with stage III disease, good performance status (0–1) and adequate lung function (FEV1 > 1.0 L and CO diffusion capacity > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. Radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to 68 Gy (A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week.

    Results: A pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011–2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in arm B compared to the encouraging results of 28 and 45 months in the standard arm. The 1- and 3-year survival rates were 56% and 33% (B) and 72% and 56% (A), respectively. There were seven toxicity-related deaths due to esophageal perforations and pneumonitis: five in the escalated group and two with standard treatment.

    Conclusion: Dose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 3-year survival of 56% (NCT01664663).

  • 33.
    Heath, Alicia K.
    et al.
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Muller, David C.
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    van den Brandt, Piet A.
    Department of Epidemiology, Maastricht University Medical Centre, Maastricht, Netherlands.
    Critselis, Elena
    Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Department of Nutrition and Dietetics, Harokopio University, Athens, Greece; Department of Primary Care and Population Health, University of Nicosia Medical School, Nicosia, Cyprus.
    Gunter, Marc
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Vineis, Paolo
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Weiderpass, Elisabete
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Boeing, Heiner
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Bergholz-Rehbrücke, Germany.
    Ferrari, Pietro
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Merritt, Melissa A.
    Cancer Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States.
    Rostgaard-Hansen, Agnetha L.
    Danish Cancer Society Research Center, Copenhagen, Denmark.
    Tjønneland, Anne
    Danish Cancer Society Research Center, Copenhagen, Denmark.
    Overvad, Kim
    Department of Public Health, Aarhus University, Aarhus, Denmark.
    Katzke, Verena
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Srour, Bernard
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Masala, Giovanna
    Institute of Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
    Sacerdote, Carlotta
    Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital, Turin, Italy.
    Ricceri, Fulvio
    Department of Clinical and Biological Sciences, University of Turin, Turin, Italy; Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Italy.
    Pasanisi, Fabrizio
    Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
    Bueno-de-Mesquita, Bas
    Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.
    Downward, George S.
    Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, Utrecht, Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
    Skeie, Guri
    Department of Community Medicine, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.
    Sandanger, Torkjel M.
    Department of Community Medicine, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.
    Crous-Bou, Marta
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Department of Epidemiology, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Rodríguez-Barranco, Miguel
    Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
    Amiano, Pilar
    Ministry of Health of the Basque Government, Sub-Directorate for Public Health and Addictions of Gipuzkoa, San Sebastián, Spain; Biodonostia Health Research Institute, Epidemiology and Public Health Area, San Sebastián, Spain; CIBER Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
    Huerta, José María
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
    Ardanaz, Eva
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Navarra Public Health Institute, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
    Drake, Isabel
    Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Key, Tim
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Papadimitriou, Nikos
    Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
    Riboli, Elio
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Tzoulaki, Ioanna
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
    Tsilidis, Konstantinos K.
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
    Diet-wide association study of 92 foods and nutrients and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study2022In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 151, no 11, p. 1935-1946Article in journal (Refereed)
    Abstract [en]

    It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327 790 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per SD higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2420 incident lung cancer cases were identified during a median of 15 years of follow-up. Higher intakes of fibre (HR per 1 SD higher intake/day = 0.91, 95% CI 0.87-0.96), fruit (HR = 0.91, 95% CI 0.86-0.96) and vitamin C (HR = 0.91, 95% CI 0.86-0.96) were associated with a lower risk of lung cancer, whereas offal (HR = 1.08, 95% CI 1.03-1.14), retinol (HR = 1.06, 95% CI 1.03-1.10) and beer/cider (HR = 1.04, 95% CI 1.02-1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer.

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  • 34.
    Henriksson, Roger
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergström, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sandström, Maria
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enigma of a rapid introduction of antiangiogenic therapy with bevacizumab in glioblastoma: a new era in the treatment of malignant brain tumours?2009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 1, p. 6-8Article in journal (Other academic)
  • 35.
    Henriksson, Roger
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Fredrik
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Asklund, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Blomquist, Erik
    Bergström, Stefan
    Ekman, Simon
    Bergqvist, Michael
    Brain Tumors - Prognostic and Predictive Markers2009In: Histological and Serological Tumor Markers and Gene Expression and Their Clinical Usefulness in Cancers / [ed] Dan Hellberg, Hauppauge: Nova Science Publishers, Inc., 2009, p. 53-75Chapter in book (Refereed)
    Abstract [en]

    This review summarizes the status of prognostic and predictive markers in brain tumors with a focus on the most frequent tumors, gliomas. Brain tumors are a heterogeneous group of different tumors with a huge variation in outcome. Although the most common tumor, high-grade malignant glioma, still has a dismal prognosis, the last years have seen a significant improvement in the management in this tumor as well as in most other brain tumors. Age, tumor grade and KPS are still the most reliable prognostic and predictive variables available for patients with brain tumors. Although chromosome 1p/19q co-deletion and methylation status of the promoter of the MGMT gene (encoding O6-methylguanine-DNA methyl transferase) have been identified as the most promising potential predictors of response to chemotherapy in malignant gliomas, there are as yet no reliable biomarkers for tumour grading or tumour monitoring in the clinical setting.

  • 36. Huang, Joyce Y.
    et al.
    Larose, Tricia L.
    Luu, Hung N.
    Wang, Renwei
    Fanidi, Anouar
    Alcala, Karine
    Stevens, Victoria L.
    Weinstein, Stephanie J.
    Albanes, Demetrius
    Caporaso, Neil E.
    Purdue, Mark P.
    Ziegler, Regina G.
    Freedman, Neal D.
    Lan, Qing
    Prentice, Ross L.
    Pettinger, Mary
    Thomson, Cynthia A.
    Cai, Qiuyin
    Wu, Jie
    Blot, William J.
    Shu, Xiao-Ou
    Zheng, Wei
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    Le Marchand, Loic
    Wilkens, Lynn R.
    Haiman, Christopher A.
    Zhang, Xuehong
    Stampfer, Meir J.
    Giles, Graham G.
    Hodge, Allison M.
    Severi, Gianluca
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Langhammer, Arnulf
    Hveem, Kristian
    Xiang, Yong-Bing
    Li, Hong-Lan
    Gao, Yu-Tang
    Visvanathan, Kala
    Ueland, Per M.
    Midttun, Oivind
    Ulvi, Arve
    Buring, Julie E.
    Lee, I-Min
    SeSS, Howard D.
    Gaziano, J. Michael
    Manjer, Jonas
    Relton, Caroline
    Koh, Woon-Puay
    Brennan, Paul
    Johansson, Mattias
    Yuan, Jian-Min
    Han, Jiali
    Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)2020In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 9, p. 2394-2405Article in journal (Refereed)
    Abstract [en]

    Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p(trend) < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

  • 37.
    Isaksson, Johan
    et al.
    Department of Immunology Genetics and Pathology, Science for life laboratory, Uppsala University, Uppsala, Sweden; Center for Research and Development, Uppsala University/Region Gävleborg, Uppsala, Sweden.
    Berglund, Anders
    Epistat AB, Uppsala, Sweden.
    Louie, Karly
    Amgen Ltd, Uxbridge, United Kingdom.
    Willén, Linda
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Center for Research and Development, Uppsala University/Region Gävleborg, Uppsala, Sweden.
    Hamidian, Arash
    Amgen Sweden AB, Solna, Sweden.
    Edsjö, Anders
    Division of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Enlund, Fredrik
    Diagnostic center, Region Kalmar County, Sweden.
    Planck, Maria
    Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    Vikström, Anders
    Department of Pulmonary Medicine, Linköping University Hospital, Linköping, Sweden.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallqvist, Andreas
    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Wagenius, Gunnar
    Cancer Theme, Karolinska University Hospital, Stockholm, Sweden.
    Botling, Johan
    Department of Immunology Genetics and Pathology, Science for life laboratory, Uppsala University, Uppsala, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    KRAS G12C mutant non–small cell lung cancer linked to female sex and high risk of cns metastasis: population-based demographics and survival data from the national swedish lung cancer registry2023In: Clinical Lung Cancer, ISSN 1525-7304, E-ISSN 1938-0690, Vol. 24, no 6, p. 507-518Article in journal (Refereed)
    Abstract [en]

    Background: Real-world data on demographics related to KRAS mutation subtypes are crucial as targeted drugs against the p.G12C variant have been approved.

    Method: We identified 6183 NSCLC patients with reported NGS-based KRAS status in the Swedish national lung cancer registry between 2016 and 2019. Following exclusion of other targetable drivers, three cohorts were studied: KRAS-G12C (n = 848), KRAS-other (n = 1161), and driver negative KRAS-wild-type (wt) (n = 3349).

    Results: The prevalence of KRAS mutations and the p.G12C variant respectively was 38%/16% in adenocarcinoma, 28%/13% in NSCLC-NOS and 6%/2% in squamous cell carcinoma. Women were enriched in the KRAS-G12C (65%) and KRAS-other (59%) cohorts versus KRAS-wt (48%). A high proportion of KRAS-G12C patients in stage IV (28%) presented with CNS metastasis (vs. KRAS-other [19%] and KRAS-wt [18%]). No difference in survival between the mutation cohorts was seen in stage I-IIIA. In stage IV, median overall survival (mOS) from date of diagnosis was shorter for KRAS-G12C and KRAS-other (5.8 months/5.2 months) vs. KRAS wt (6.4 months). Women had better outcome in the stage IV cohorts, except in KRAS-G12C subgroup where mOS was similar between men and women. Notably, CNS metastasis did not impact survival in stage IV KRAS-G12C, but was associated with poorer survival, as expected, in KRAS-other and KRAS-wt.

    Conclusion: The KRAS p.G12C variant is a prevalent targetable driver in Sweden and significantly associated with female sex and presence of CNS metastasis. We show novel survival effects linked to KRAS p.G12C mutations in these subgroups with implications for clinical practice.

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  • 38. Ji, Xuemei
    et al.
    Bosse, Yohan
    Landi, Maria Teresa
    Gui, Jiang
    Xiao, Xiangjun
    Qian, David
    Joubert, Philippe
    Lamontagne, Maxime
    Li, Yafang
    Gorlov, Ivan
    de Biasi, Mariella
    Han, Younghun
    Gorlova, Olga
    Hung, Rayjean J.
    Wu, Xifeng
    Mckay, James
    Zong, Xuchen
    Carreras-Torres, Robert
    Christiani, David C.
    Caporaso, Neil
    Johansson, Mattias
    Liu, Geoffrey
    Bojesen, Stig E.
    Le Marchand, Loic
    Albanes, Demetrios
    Bickeboeller, Heike
    Aldrich, Melinda C.
    Bush, William S.
    Tardon, Adonina
    Rennert, Gad
    Chen, Chu
    Teare, M. Dawn
    Field, John K.
    Kiemeney, Lambertus A.
    Lazarus, Philip
    Haugen, Aage
    Lam, Stephen
    Schabath, Matthew B.
    Andrew, Angeline S.
    Shen, Hongbing
    Hong, Yun-Chul
    Yuan, Jian-Min
    Bertazzi, Pier A.
    Pesatori, Angela C.
    Ye, Yuanqing
    Diao, Nancy
    Su, Li
    Zhang, Ruyang
    Brhane, Yonathan
    Leighl, Natasha
    Johansen, Jakob S.
    Mellemgaard, Anders
    Saliba, Walid
    Haiman, Christopher
    Wilkens, Lynne
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    van der Heijden, Erik H. F. M.
    Kim, Jin Hee
    Dai, Juncheng
    Hu, Zhibin
    Davies, Michael P. A.
    Marcus, Michael W.
    Brunnstrom, Hans
    Manjer, Jonas
    Melander, Olle
    Muller, David C.
    Overvad, Kim
    Trichopoulou, Antonia
    Tumino, Rosario
    Doherty, Jennifer
    Goodman, Gary E.
    Cox, Angela
    Taylor, Fiona
    Woll, Penella
    Brueske, Irene
    Manz, Judith
    Muley, Thomas
    Risch, Angela
    Rosenberger, Albert
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Shepherd, Frances
    Tsao, Ming-Sound
    Arnold, Susanne M.
    Haura, Eric B.
    Bolca, Ciprian
    Holcatova, Ivana
    Janout, Vladimir
    Kontic, Milica
    Lissowska, Jolanta
    Mukeria, Anush
    Ognjanovic, Simona
    Orlowski, Tadeusz M.
    Scelo, Ghislaine
    Swiatkowska, Beata
    Zaridze, David
    Bakke, Per
    Skaug, Vidar
    Zienolddiny, Shanbeh
    Duell, Eric J.
    Butler, Lesley M.
    Koh, Woon-Puay
    Gao, Yu-Tang
    Houlston, Richard
    McLaughlin, John
    Stevens, Victoria
    Nickle, David C.
    Obeidat, Ma'en
    Timens, Wim
    Zhu, Bin
    Song, Lei
    Artigas, Maria Soler
    Tobin, Martin D.
    Wain, Louise V.
    Gu, Fangyi
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Tyndale, Rachel F.
    Wei, Wei-Qi
    Chanock, Stephen
    Brennan, Paul
    Amos, Christopher I.
    Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk2018In: Nature Communications, E-ISSN 2041-1723, Vol. 9, p. 1-15, article id 3221Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

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  • 39. Ji, Xuemei
    et al.
    Mukherjee, Semanti
    Landi, Maria Teresa
    Bosse, Yohan
    Joubert, Philippe
    Zhu, Dakai
    Gorlov, Ivan
    Xiao, Xiangjun
    Han, Younghun
    Gorlova, Olga
    Hung, Rayjean J.
    Brhane, Yonathan
    Carreras-Torres, Robert
    Christiani, David C.
    Caporaso, Neil
    Johansson, Mattias
    Liu, Geoffrey
    Bojesen, Stig E.
    Le Marchand, Loic
    Albanes, Demetrios
    Bickeboeller, Heike
    Aldrich, Melinda C.
    Bush, William S.
    Tardon, Adonina
    Rennert, Gad
    Chen, Chu
    Byun, Jinyoung
    Dragnev, Konstantin H.
    Field, John K.
    Kiemeney, Lambertus F. A.
    Lazarus, Philip
    Zienolddiny, Shan
    Lam, Stephen
    Schabath, Matthew B.
    Andrew, Angeline S.
    Bertazzi, Pier A.
    Pesatori, Angela C.
    Diao, Nancy
    Su, Li
    Song, Lei
    Zhang, Ruyang
    Leighl, Natasha
    Johansen, Jakob S.
    Mellemgaard, Anders
    Saliba, Walid
    Haiman, Christopher
    Wilkens, Lynne
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    van der Heijden, Erik H. F. M.
    Kim, Jin Hee
    Davies, Michael P. A.
    Marcus, Michael W.
    Brunnstrom, Hans
    Manjer, Jonas
    Melander, Olle
    Muller, David C.
    Overvad, Kim
    Trichopoulou, Antonia
    Tumino, Rosario
    Goodman, Gary E.
    Cox, Angela
    Taylor, Fiona
    Woll, Penella
    Wichmann, Erich
    Muley, Thomas
    Risch, Angela
    Rosenberger, Albert
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tsao, Ming-Sound
    Shepherd, Frances
    Arnold, Susanne M.
    Haura, Eric B.
    Bolca, Ciprian
    Holcatova, Ivana
    Janout, Vladimir
    Kontic, Milica
    Lissowska, Jolanta
    Mukeria, Anush
    Ognjanovic, Simona
    Orlowski, Tadeusz M.
    Scelo, Ghislaine
    Swiatkowska, Beata
    Zaridze, David
    Bakke, Per
    Skaug, Vidar
    Butler, Lesley M.
    Offit, Kenneth
    Srinivasan, Preethi
    Bandlamudi, Chaitanya
    Hellmann, Matthew D.
    Solit, David B.
    Robson, Mark E.
    Rudin, Charles M.
    Stadler, Zsofia K.
    Taylor, Barry S.
    Berger, Michael F.
    Houlston, Richard
    McLaughlin, John
    Stevens, Victoria
    Nickle, David C.
    Obeidat, 'en
    Timens, Wim
    Artigas, Maria Soler
    Shete, Sanjay
    Brenner, Hermann
    Chanock, Stephen
    Brennan, Paul
    McKay, James D.
    Amos, Christopher, I
    Protein-altering germline mutations implicate novel genes related to lung cancer development2020In: Nature Communications, E-ISSN 2041-1723, Vol. 11, no 1, article id 2220Article in journal (Refereed)
    Abstract [en]

    Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

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  • 40. Jiang, Xia
    et al.
    Finucane, Hilary K.
    Schumacher, Fredrick R.
    Schmit, Stephanie L.
    Tyrer, Jonathan P.
    Han, Younghun
    Michailidou, Kyriaki
    Lesseur, Corina
    Kuchenbaecker, Karoline B.
    Dennis, Joe
    Conti, David V.
    Casey, Graham
    Gaudet, Mia M.
    Huyghe, Jeroen R.
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline S.
    Andrulis, Irene L.
    Anton-Culver, Hoda
    Antoniou, Antonis C.
    Antonenkova, Natalia N.
    Arnold, Susanne M.
    Aronson, Kristan J.
    Arun, Banu K.
    Bandera, Elisa V.
    Barkardottir, Rosa B.
    Barnes, Daniel R.
    Batra, Jyotsna
    Beckmann, Matthias W.
    Benitez, Javier
    Benlloch, Sara
    Berchuck, Andrew
    Berndt, Sonja I.
    Bickeboeller, Heike
    Bien, Stephanie A.
    Blomqvist, Carl
    Boccia, Stefania
    Bogdanova, Natalia V.
    Bojesen, Stig E.
    Bolla, Manjeet K.
    Brauch, Hiltrud
    Brenner, Hermann
    Brenton, James D.
    Brook, Mark N.
    Brunet, Joan
    Brunnstrom, Hans
    Buchanan, Daniel D.
    Burwinkel, Barbara
    Butzow, Ralf
    Cadoni, Gabriella
    Caldes, Trinidad
    Caligo, Maria A.
    Campbell, Ian
    Campbell, Peter T.
    Cancel-Tassin, Geraldine
    Cannon-Albright, Lisa
    Campa, Daniele
    Caporaso, Neil
    Carvalho, Andre L.
    Chan, Andrew T.
    Chang-Claude, Jenny
    Chanock, Stephen J.
    Chen, Chu
    Christiani, David C.
    Claes, Kathleen B. M.
    Claessens, Frank
    Clements, Judith
    Collee, J. Margriet
    Correa, Marcia Cruz
    Couch, Fergus J.
    Cox, Angela
    Cunningham, Julie M.
    Cybulski, Cezary
    Czene, Kamila
    Daly, Mary B.
    defazio, Anna
    Devilee, Peter
    Diez, Orland
    Gago-Dominguez, Manuela
    Donovan, Jenny L.
    Doerk, Thilo
    Duell, Eric J.
    Dunning, Alison M.
    Dwek, Miriam
    Eccles, Diana M.
    Edlund, Christopher K.
    Edwards, Digna R. Velez
    Ellberg, Carolina
    Evans, D. Gareth
    Fasching, Peter A.
    Ferris, Robert L.
    Liloglou, Triantafillos
    Figueiredo, Jane C.
    Fletcher, Olivia
    Fortner, Renee T.
    Fostira, Florentia
    Franceschi, Silvia
    Friedman, Eitan
    Gallinger, Steven J.
    Ganz, Patricia A.
    Garber, Judy
    Garcia-Saenz, Jose A.
    Gayther, Simon A.
    Giles, Graham G.
    Godwin, Andrew K.
    Goldberg, Mark S.
    Goldgar, David E.
    Goode, Ellen L.
    Goodman, Marc T.
    Goodman, Gary
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Greene, Mark H.
    Gronberg, Henrik
    Gronwald, Jacek
    Guenel, Pascal
    Hakansson, Niclas
    Hall, Per
    Hamann, Ute
    Hamdy, Freddie C.
    Hamilton, Robert J.
    Hampe, Jochen
    Haugen, Aage
    Heitz, Florian
    Herrero, Rolando
    Hillemanns, Peter
    Hoffmeister, Michael
    Hogdall, Estrid
    Hong, Yun-Chul
    Hopper, John L.
    Houlston, Richard
    Hulick, Peter J.
    Hunter, David J.
    Huntsman, David G.
    Idos, Gregory
    Imyanitov, Evgeny N.
    Ingles, Sue Ann
    Isaacs, Claudine
    Jakubowska, Anna
    James, Paul
    Jenkins, Mark A.
    Johansson, Mattias
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    John, Esther M.
    Joshi, Amit D.
    Kaneva, Radka
    Karlan, Beth Y.
    Kelemen, Linda E.
    Kuhl, Tabea
    Khaw, Kay-Tee
    Khusnutdinova, Elza
    Kibel, Adam S.
    Kiemeney, Lambertus A.
    Kim, Jeri
    Kjaer, Susanne K.
    Knight, Julia A.
    Kogevinas, Manolis
    Kote-Jarai, Zsofia
    Koutros, Stella
    Kristensen, Vessela N.
    Kupryjanczyk, Jolanta
    Lacko, Martin
    Lam, Stephan
    Lambrechts, Diether
    Landi, Maria Teresa
    Lazarus, Philip
    Le, Nhu D.
    Lee, Eunjung
    Lejbkowicz, Flavio
    Lenz, Heinz-Josef
    Leslie, Goska
    Lessel, Davor
    Lester, Jenny
    Levine, Douglas A.
    Li, Li
    Li, Christopher I.
    Lindblom, Annika
    Lindor, Noralane M.
    Liu, Geoffrey
    Loupakis, Fotios
    Lubinski, Jan
    Maehle, Lovise
    Maier, Christiane
    Mannermaa, Arto
    Le Marchand, Loic
    Margolin, Sara
    May, Taymaa
    McGuffog, Lesley
    Meindl, Alfons
    Middha, Pooja
    Miller, Austin
    Milne, Roger L.
    MacInnis, Robert J.
    Modugno, Francesmary
    Montagna, Marco
    Moreno, Victor
    Moysich, Kirsten B.
    Mucci, Lorelei
    Muir, Kenneth
    Mulligan, Anna Marie
    Nathanson, Katherine L.
    Neal, David E.
    Ness, Andrew R.
    Neuhausen, Susan L.
    Nevanlinna, Heli
    Newcomb, Polly A.
    Newcomb, Lisa F.
    Nielsen, Finn Cilius
    Nikitina-Zake, Liene
    Nordestgaard, Borge G.
    Nussbaum, Robert L.
    Offit, Kenneth
    Olah, Edith
    Al Olama, Ali Amin
    Olopade, Olufunmilayo I.
    Olshan, Andrew F.
    Olsson, Hakan
    Osorio, Ana
    Pandha, Hardev
    Park, Jong Y.
    Pashayan, Nora
    Parsons, Michael T.
    Pejovic, Tanja
    Penney, Kathryn L.
    Peters, Wilbert H. M.
    Phelan, Catherine M.
    Phipps, Amanda I.
    Plaseska-Karanfilska, Dijana
    Pring, Miranda
    Prokofyeva, Darya
    Radice, Paolo
    Stefansson, Kari
    Ramus, Susan J.
    Raskin, Leon
    Rennert, Gad
    Rennert, Hedy S.
    van Rensburg, Elizabeth J.
    Riggan, Marjorie J.
    Risch, Harvey A.
    Risch, Angela
    Roobol, Monique J.
    Rosenstein, Barry S.
    Rossing, Mary Anne
    De Ruyck, Kim
    Saloustros, Emmanouil
    Sandler, Dale P.
    Sawyer, Elinor J.
    Schabath, Matthew B.
    Schleutker, Johanna
    Schmidt, Marjanka K.
    Setiawan, V. Wendy
    Shen, Hongbing
    Siegel, Erin M.
    Sieh, Weiva
    Singer, Christian F.
    Slattery, Martha L.
    Sorensen, Karina Dalsgaard
    Southey, Melissa C.
    Spurdle, Amanda B.
    Stanford, Janet L.
    Stevens, Victoria L.
    Stintzing, Sebastian
    Stone, Jennifer
    Sundfeldt, Karin
    Sutphen, Rebecca
    Swerdlow, Anthony J.
    Tajara, Eloiza H.
    Tangen, Catherine M.
    Tardon, Adonina
    Taylor, Jack A.
    Teare, M. Dawn
    Teixeira, Manuel R.
    Terry, Mary Beth
    Terry, Kathryn L.
    Thibodeau, Stephen N.
    Thomassen, Mads
    Bjorge, Line
    Tischkowitz, Marc
    Toland, Amanda E.
    Torres, Diana
    Townsend, Paul A.
    Travis, Ruth C.
    Tung, Nadine
    Tworoger, Shelley S.
    Ulrich, Cornelia M.
    Usmani, Nawaid
    Vachon, Celine M.
    Van Nieuwenhuysen, Els
    Vega, Ana
    Aguado-Barrera, Miguel Elias
    Wang, Qin
    Webb, Penelope M.
    Weinberg, Clarice R.
    Weinstein, Stephanie
    Weissler, Mark C.
    Weitzel, Jeffrey N.
    West, Catharine M. L.
    White, Emily
    Whittemore, Alice S.
    Wichmann, H-Erich
    Wiklund, Fredrik
    Winqvist, Robert
    Wolk, Alicja
    Woll, Penella
    Woods, Michael
    Wu, Anna H.
    Wu, Xifeng
    Yannoukakos, Drakoulis
    Zheng, Wei
    Zienolddiny, Shanbeh
    Ziogas, Argyrios
    Zorn, Kristin K.
    Lane, Jacqueline M.
    Saxena, Richa
    Thomas, Duncan
    Hung, Rayjean J.
    Diergaarde, Brenda
    Mckay, James
    Peters, Ulrike
    Hsu, Li
    Garcia-Closas, Montserrat
    Eeles, Rosalind A.
    Chenevix-Trench, Georgia
    Brennan, Paul J.
    Haiman, Christopher A.
    Simard, Jacques
    Easton, Douglas F.
    Gruber, Stephen B.
    Pharoah, Paul D. P.
    Price, Alkes L.
    Pasaniuc, Bogdan
    Amos, Christopher I.
    Kraft, Peter
    Lindstrom, Sara
    Shared heritability and functional enrichment across six solid cancers2019In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 431Article in journal (Refereed)
    Abstract [en]

    Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

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  • 41.
    Johansson, Mikael
    et al.
    Departments of Oncology, University Hospital, Umeå, Sweden.
    Bergenheim, A. Tommy
    Departments of Oncology, University Hospital, Umea, Sweden. Neurosurgery, University Hospital, Umeå, Sweden.
    Henriksson, Roger
    Departments of Oncology, University Hospital, Umea, Sweden.
    Koskinen, Lars-Owe D.
    Neurosurgery, University Hospital, Umeå, Sweden.
    Vallbo, Christina
    Departments of Oncology, University Hospital, Umea, Sweden.
    Widmark, Anders
    Departments of Oncology, University Hospital, Umea, Sweden.
    Tumor blood flow and the cytotoxic effects of estramustine and its constituents in a rat glioma model1997In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 41, no 1, p. 237-244Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Estramustine (EaM) is a conjugate of nor-nitrogen mustard (NNM) and 17 beta-estradiol (E2) that has cytotoxic and radiosensitizing effects on experimental malignant glioma. Its mechanism of action is only partly understood. To further investigate the mechanism in vivo, the effects on tumor blood flow (TBF) and tumor growth were analyzed.

    METHODS: TBF was measured by radioactive microspheres, and tumor growth was measured by weight. Apoptosis was evaluated by in situ end labeling and gel electrophoresis. The effects of the constituents NNM and E2 were also evaluated.

    RESULTS: EaM increased TBF to 153.8 ml/100 g/min after 3 days and to 153.9 ml/100 g/min after 10 days of treatment, compared with 94.0 ml/100 g/min in untreated controls. Cerebral blood flow did not change after EaM treatment. NNM increased TBF but also showed a tendency to increase cerebral blood flow. E2 increased TBF, whereas cerebral blood flow was unchanged. EaM resulted in a rapid reduction in tumor weight from 230 mg in untreated animals to 146 mg after 3 days of treatment. EaM induced an early transient fragmentation of deoxyribonucleic acid in glioma but not in the normal brain. Neither NNM nor E2 affected tumor weight.

    CONCLUSION: EaM increases TBF in the BT4C rat glioma model with a concomitant rapid antitumoral effect. The increase in TBF could partially be induced by an estrogen-like action of EaM, but the rapid cytotoxic effect of the drug is obviously attributed to the intact EaM compound. This cytotoxic effect might be attributable to the induction of programmed cell death.

  • 42.
    Johansson, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Oudin, Anaïs
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Tiemann, Katja
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Bernard, Amandine
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Golebiewska, Anna
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Keunen, Olivier
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Fack, Fred
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Stieber, Daniel
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    Wang, Baofeng
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Niclou, Simone P.
    NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg.
    The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status2013In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, no 9, p. 1200-1211Article in journal (Refereed)
    Abstract [en]

    Deregulated growth factor signaling is a major driving force in the initiation and progression of glioblastoma. The tumor suppressor and stem cell marker Lrig1 is a negative regulator of the epidermal growth factor receptor (EGFR) family. Here, we addressed the therapeutic potential of the soluble form of Lrig1 (sLrig1) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition. With use of encapsulated cells, recombinant sLrig1 was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrig1 and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a constitutively active EGFR mutant (EGFRvIII). Continuous interstitial delivery of sLrig1 in genetically diverse patient-derived glioma xenografts led to strong tumor growth inhibition. Glioma cell proliferation in vitro and tumor growth in vivo were potently inhibited by sLrig1, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvIII-driven glioma. sLrig1 induced cell cycle arrest without changing total receptor level or phosphorylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrig1 into established tumors led to a 32 survival advantage in treated mice. To our knowledge, this is the first report demonstrating that sLrig1 is a potent inhibitor of glioblastoma growth in clinically relevant experimental glioma models and that this effect is largely independent of EGFR status. The potent anti-tumor effect of sLrig1, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.

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  • 43.
    Johansson, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Oudin, Anaïs
    Tiemann, Katja
    Bernard, Amandine
    Keunen, Olivier
    Fack, Fred
    Golebiewska, Anna
    Stieber, Daniel
    Wang, Baofeng
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Niclou, Simone P.
    The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl. 3, p. 15-16Article in journal (Other academic)
  • 44. Kachuri, Linda
    et al.
    Amos, Christopher I.
    Mckay, James D.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Vineis, Paolo
    Bueno-de-Mesquita, H. Bas
    Boutron-Ruault, Marie-Christine
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Quiros, J. Ramon
    Sieri, Sabina
    Travis, Ruth C.
    Weiderpass, Elisabete
    Le Marchand, Loic
    Henderson, Brian E.
    Wilkens, Lynne
    Goodman, Gary E.
    Chen, Chu
    Doherty, Jennifer A.
    Christiani, David C.
    Wei, Yongyue
    Su, Li
    Tworoger, Shelley
    Zhang, Xuehong
    Kraft, Peter
    Zaridze, David
    Field, John K.
    Marcus, Michael W.
    Davies, Michael P. A.
    Hyde, Russell
    Caporaso, Neil E.
    Landi, Maria Teresa
    Severi, Gianluca
    Giles, Graham G.
    Liu, Geoffrey
    McLaughlin, John R.
    Li, Yafang
    Xiao, Xiangjun
    Fehringer, Gord
    Zong, Xuchen
    Denroche, Robert E.
    Zuzarte, Philip C.
    McPherson, John D.
    Brennan, Paul
    Hung, Rayjean J.
    Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 1, p. 96-105Article in journal (Refereed)
    Abstract [en]

    Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64x10(-6)), rs112290073 (OR = 1.85, P = 1.27x10(-5)), rs138895564 (OR = 2.16, P = 2.06x10(-5); among young cases, OR = 3.77, P = 8.41x10(-4)). In addition, we found that rs139852726 (P = 1.44x10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84x10(-7)) and lung cancer (P = 2.37x10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.

  • 45. Karlsson, Anna
    et al.
    Cirenajwis, Helena
    Ericson-Lindquist, Kajsa
    Brunnström, Hans
    Reuterswärd, Christel
    Jönsson, Mats
    Ortiz-Villalon, Cristian
    Hussein, Aziz
    Bergman, Bengt
    Vikström, Anders
    Monsef, Nastaran
    Branden, Eva
    Koyi, Hirsh
    de Petris, Luigi
    Micke, Patrick
    Patthey, Annika
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Planck, Maria
    Staaf, Johan
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 5207Article in journal (Refereed)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

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  • 46.
    Karlsson, Terese
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Botling, J
    Micke, P
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LMO7 interacts with LRIG proteins, and is a negative prognostic marker in lung cancerManuscript (preprint) (Other academic)
  • 47.
    Karlsson, Terese
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Botling, Johan
    Micke, Patrick
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease2018In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, p. 174-184Article in journal (Refereed)
    Abstract [en]

    Objectives: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.

    Materials and methods: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.

    Results: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.

    Conclusion: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.

  • 48.
    Karlsson, Terese
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Botling, Johan
    Micke, Patrick
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Interactions between LRIG proteins and LMO7 and the expression of LMO7 in human lung cancer.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8: suppl 1, p. 5315-Article in journal (Refereed)
  • 49. Keunen, Olivier
    et al.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Oudin, Anaïs
    Sanzey, Morgane
    Rahim, Siti A Abdul
    Fack, Fred
    Thorsen, Frits
    Taxt, Torfinn
    Bartos, Michal
    Jirik, Radovan
    Miletic, Hrvoje
    Wang, Jian
    Stieber, Daniel
    Stuhr, Linda
    Moen, Ingrid
    Brekke Rygh, Cecilie
    Bjerkvig, Rolf
    Niclou, Simone P
    Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 9, p. 3749-3754Article in journal (Refereed)
    Abstract [en]

    Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.

  • 50.
    Kouremenos, Konstantinos A
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Marriott, Philip J
    Monash University, Victoria, Australia.
    Advances in gas chromatographic methods for the identification of biomarkers in cancer2012In: Journal of Cancer, E-ISSN 1837-9664, Vol. 3, p. 404-420Article in journal (Refereed)
    Abstract [en]

    Screening complex biological specimens such as exhaled air, tissue, blood and urine to identify biomarkers in different forms of cancer has become increasingly popular over the last decade, mainly due to new instruments and improved bioinformatics. However, despite some progress, the identification of biomarkers has shown to be a difficult task with few new biomarkers (excluding recent genetic markers) being considered for introduction to clinical analysis. This review describes recent advances in gas chromatographic methods for the identification of biomarkers in the detection, diagnosis and treatment of cancer. It presents a general overview of cancer metabolism, the current biomarkers used for cancer diagnosis and treatment, a background to metabolic changes in tumors, an overview of current GC methods, and collectively presents the scope and outlook of GC methods in oncology.

    Download full text (pdf)
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