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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.

  • 4. 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.

  • 5. Brenner, Darren R.
    et al.
    Fanidi, Anouar
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    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.

  • 6. 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.

  • 7. 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.
    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.
    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.

  • 8. 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.

  • 9.
    Eriksson, M
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    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]

    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.

  • 10.
    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.

  • 11.
    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.
    Blomqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    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, ISSN 2041-4889, 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.

     

     

  • 12.
    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)
  • 13. 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.

  • 14. 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.

  • 15. 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.

  • 16. 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, ISSN 2041-1723, 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.

  • 17. 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.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    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, ISSN 2041-1723, 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.

  • 18. 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.

  • 19. Hallqvist, Andreas
    et al.
    Bergstrom, Stefan
    Bjorkestrand, Hedvig
    Svärd, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ekman, Simon
    Lundin, Erik
    Holmberg, Erik
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Friesland, Signe
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    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).

  • 20.
    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)
  • 21.
    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.

  • 22. 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)2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article 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.

  • 23. 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, ISSN 2041-1723, 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.

  • 24. 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.
    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, ISSN 2041-1723, 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.

  • 25.
    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.

  • 26.
    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)
  • 27. 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.

  • 28. 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, ISSN 2045-2322, 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.

  • 29.
    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)
  • 30.
    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.

  • 31.
    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)
  • 32. 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.

  • 33.
    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, ISSN 1837-9664, 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.

  • 34.
    Kvarnbrink, Samuel
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Karlsson, Terese
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Edlund, Karolina
    Botling, Johan
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirström, Karin
    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.
    LRIG1 is a prognostic biomarker in non-small cell lung cancer2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 8, p. 1113-1119Article in journal (Refereed)
    Abstract [en]

    Background: The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins are involved in the regulation of cellular signal transduction. LRIG1 is an endogenous inhibitor of receptor tyrosine kinases (RTKs) and an emerging tumor suppressor. In the lung epithelium, the expression of LRIG1 is downregulated by tobacco smoking, and further downregulated in lung squamous cell carcinoma. Material and methods: The expression of LRIG proteins were analyzed in 347 cases of non-small cell lung cancer (NSCLC) by immunohistochemistry, and LRIG1 mRNA expression was evaluated in 807 lung cancer samples in silico in the Oncomine database. Potential associations between the expression data and the clinical parameters, including patient survival, were investigated. Results: Expression of the LRIG1 protein was found to be an independent prognostic factor in NSCLC, whereas expression of LRIG2 or LRIG3 did not correlate with patient survival. The levels of LRIG1 mRNA also correlated with the survival of NSCLC patients. Conclusion: These findings demonstrate that LRIG1 is an independent prognostic factor in patients with NSCLC that could be important in future decision-making algorithms for adjuvant lung cancer treatment.

  • 35.
    Kvarnbrink, Samuel
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Karlsson, Terese
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Forssell, Joakim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Faraz, Mahmood
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Botling, J
    Feng, Mao
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Micke, P
    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.
    LRIG1 is a prognostic biomarker and tumor suppressor in non-small cell lung cancerManuscript (preprint) (Other academic)
  • 36.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    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.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Liquid biopsies in lung cancer: time to implement research technologies in routine care?2017In: Annals of Translational Medicine, ISSN 2305-5839, E-ISSN 2305-5847, Vol. 5, no 13, article id 278Article, review/survey (Refereed)
    Abstract [en]

    Lung cancer is the leading cause of cancer mortality. A substantial progress in the understanding of lung cancer biology has resulted in several promising targeted therapies for advanced disease. Druggable targets today include point mutations such as EGFR, BRAF and re-arrangements in genes such as ALK and ROS1. Liquid biopsies collecting e.g., circulating tumor DNA (ctDNA) reflects overall tumor information and is not biased by analyzing of only a small fraction of the tumor and is always accessible in contrast to the lung cancer tissue. Technological advances in detection of low frequency mutation variants in ctDNA have made it the dominating liquid biopsy platform in terms of utility and sensitivity. Circulating DNA or RNA may possible be used to define populations with higher risk of developing lung cancer, thus reducing screening cohorts and increasing the positive predictive value of screening. Blood based-tests may also aid to identify genetic alterations several weeks prior to radiologically verified recurrence and may be of great value in the follow-up of lung cancer patients. Besides being an alternative to invasive biopsies in selected cases, liquid biopsies offer a unique possibility to monitor treatment response following medical treatment as well as treatment response and resistance development after targeted therapy, giving a possibility to modify the treatment after the genetic profile of the tumor. Ideally, genetic alterations found in ctDNA could be tracked in real-time discriminating between fast-growing life-threatening tumors from more indolent slow growing tumors or premalignant growth that are of no concern for the wellbeing of the patient. This review focuses on future perspectives of liquid biopsies in lung cancer care for different clinical settings and present current technological platforms for further discussion of possible strategies for implementation of liquid biopsies in lung cancer.

  • 37. Larose, Tricia L.
    et al.
    Guida, Florence
    Fanidi, Anouar
    Langhammer, Arnulf
    Kveem, Kristian
    Stevens, Victoria L.
    Jacobs, Eric J.
    Smith-Warner, Stephanie A.
    Giovannucci, Edward
    Albanes, Demetrius
    Weinstein, Stephanie J.
    Freedman, Neal D.
    Prentice, Ross
    Pettinger, Mary
    Thomson, Cynthia A.
    Cai, Qiuyin
    Wu, Jie
    Blot, William J.
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    Le Marchand, Loic
    Wilkens, Lynne R.
    Haiman, Christopher A.
    Zhang, Xuehong
    Stampfer, Meir J.
    Hodge, Allison M.
    Giles, Graham G.
    Severi, Gianluca
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wang, Renwei
    Yuan, Jian-Min
    Gao, Yu-Tang
    Koh, Woon-Puay
    Shu, Xiao-Ou
    Zheng, Wei
    Xiang, Yong-Bing
    Li, Honglan
    Lan, Qing
    Visvanathan, Kala
    Bolton, Judith Hoffman
    Ueland, Per Magne
    Midttun, Oivind
    Caporaso, Neil
    Purdue, Mark
    Sesso, Howard D.
    Buring, Julie E.
    Lee, I-Min
    Gaziano, J. Michael
    Manjer, Jonas
    Brunnstrom, Hans
    Brennan, Paul
    Johansson, Mattias
    Circulating cotinine concentrations and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)2018In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 47, no 6, p. 1760-1771Article in journal (Refereed)
    Abstract [en]

    Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine—a nicotine metabolite and biomarker of recent tobacco exposure—provides additional information on lung cancer risk.

    Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis.

    Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32–1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68–0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64–0.68) (P = 1.5x10–9).

    Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.

  • 38. Li, Yafang
    et al.
    Xiao, Xiangjun
    Han, Younghun
    Gorlova, Olga
    Qian, David
    Leighl, Natasha
    Johansen, Jakob S.
    Barnett, Matt
    Chen, Chu
    Goodman, Gary
    Cox, Angela
    Taylor, Fiona
    Woll, Penella
    Wichmann, H-Erich
    Manz, Judith
    Muley, Thomas
    Risch, Angela
    Rosenberger, Albert
    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.
    Houlston, Richard
    Artigas, María Soler
    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 A.
    Marcus, Michael W.
    Brunnström, Hans
    Manjer, Jonas
    Melander, Olle
    Muller, David C.
    Overvad, Kim
    Trichopoulou, Antonia
    Tumino, Rosario
    Liu, Geoffrey
    Bojesen, Stig E.
    Wu, Xifeng
    Le Marchand, Loic
    Albanes, Demetrios
    Bickeböller, Heike
    Aldrich, Melinda C.
    Bush, William S.
    Tardon, Adonina
    Rennert, Gad
    Teare, M. Dawn
    Field, John K.
    Kiemeney, Lambertus A.
    Lazarus, Philip
    Haugen, Aage
    Lam, Stephen
    Schabath, Matthew B
    Andrew, Angeline S.
    Bertazzi, Pier Alberto
    Pesatori, Angela C.
    Christiani, David C.
    Caporaso, Neil
    Johansson, Mattias
    McKay, James D.
    Brennan, Paul
    Hung, Rayjean J.
    Amos, Christopher I.
    Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population2018In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 39, no 3, p. 336-346Article in journal (Refereed)
    Abstract [en]

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between SNPs and smoking status (never vs ever smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13,336 NSCLC cases. Candidate SNPs with p-value less than 0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with p-value less than 3.5x10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 NSCLC cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis p-value for these two SNPs were 1.24 with 6.96x10-7 and 1.37 with 3.49x10-7, respectively. Additionally, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and p-value of 8.12x10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

  • 39.
    Lindgren, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Sandström, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Jonsson, Yvonne
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    VEGF and tPA co-expressed in malignant glioma1997In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 36, no 6, p. 615-618Article in journal (Refereed)
  • 40.
    Mao, Feng
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Faraz, Mahmood
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Wanzhong
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Regionalt Cancercentrum Stockholm Gotland, Karolinska, Stockholm, Sweden.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lrig1 is a haploinsufficient tumor suppressor gene in malignant glioma2018In: Oncogenesis, E-ISSN 2157-9024, Vol. 7, article id 13Article in journal (Refereed)
    Abstract [en]

    Recently, a genome-wide association study showed that a single nucleotide polymorphism (SNP) —rs11706832—in intron 2 of the human LRIG1 (Leucine-rich repeats and immunoglobulin-like domains 1) gene is associated with susceptibility to glioma. However, the mechanism by which rs11706832 affects glioma risk remains unknown; additionally, it is unknown whether the expression levels of LRIG1 are a relevant determinant of gliomagenesis. Here, we investigated the role of Lrig1 in platelet-derived growth factor (PDGF)-induced experimental glioma in mice by introducing mono-allelic and bi-allelic deletions of Lrig1 followed by inducing gliomagenesis via intracranial retroviral transduction of PDGFB in neural progenitor cells. Lrig1 was expressed in PDGFB-induced gliomas in wild-type mice as assessed using in situ hybridization. Intriguingly, Lrig1-heterozygous mice developed higher grade gliomas than did wild-type mice (grade IV vs. grade II/III, p = 0.002). Reciprocally, the ectopic expression of LRIG1 in the TB107 high-grade human glioma (glioblastoma, grade IV) cell line decreased the invasion of orthotopic tumors in immunocompromised mice in vivo and reduced cell migration in vitro. Concomitantly, the activity of the receptor tyrosine kinase MET was downregulated, which partially explained the reduction in cell migration. In summary, Lrig1 is a haploinsufficient suppressor of PDGFB-driven glioma, possibly in part via negative regulation of MET-driven cell migration and invasion. Thus, for the first time, changes in physiological Lrig1 expression have been linked to gliomagenesis, whereby the SNP rs11706832 may affect glioma risk by regulating LRIG1 expression.

  • 41. McKay, James D.
    et al.
    Hung, Rayjean J.
    Han, Younghun
    Zong, Xuchen
    Carreras-Torres, Robert
    Christiani, David C.
    Caporaso, Neil E.
    Johansson, Mattias
    Xiao, Xiangjun
    Li, Yafang
    Byun, Jinyoung
    Dunning, Alison
    Pooley, Karen A.
    Qian, David C.
    Ji, Xuemei
    Liu, Geoffrey
    Timofeeva, Maria N.
    Bojesen, Stig E.
    Wu, Xifeng
    Le Marchand, Loic
    Albanes, Demetrios
    Bickeböller, Heike
    Aldrich, Melinda C.
    Bush, William S.
    Tardon, Adonina
    Rennert, Gad
    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 Alberto
    Pesatori, Angela C.
    Ye, Yuanqing
    Diao, Nancy
    Su, Li
    Zhang, Ruyang
    Brhane, Yonathan
    Leighl, Natasha
    Johansen, Jakob S.
    Mellemgaard, Anders
    Saliba, Walid
    Haiman, Christopher A.
    Wilkens, Lynne R.
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    van der Heijden, Henricus F. M.
    Kim, Jin Hee
    Dai, Juncheng
    Hu, Zhibin
    Davies, Michael P. A.
    Marcus, Michael W.
    Brunnström, Hans
    Manjer, Jonas
    Melander, Olle
    Muller, David C.
    Overvad, Kim
    Trichopoulou, Antonia
    Tumino, Rosario
    Doherty, Jennifer A.
    Barnett, Matt P.
    Chen, Chu
    Goodman, Gary E.
    Cox, Angela
    Taylor, Fiona
    Woll, Penella
    Brüske, Irene
    Wichmann, H-Erich
    Manz, Judith
    Muley, Thomas R.
    Risch, Angela
    Rosenberger, Albert
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Shepherd, Frances A.
    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 S.
    McLaughlin, John
    Stevens, Victoria L.
    Joubert, Philippe
    Lamontagne, Maxime
    Nickle, David C.
    Obeidat, Ma'en
    Timens, Wim
    Zhu, Bin
    Song, Lei
    Kachuri, Linda
    Artigas, Maria Soler
    Tobin, Martin D.
    Wain, Louise V.
    Rafnar, Thorunn
    Thorgeirsson, Thorgeir E.
    Reginsson, Gunnar W.
    Stefansson, Kari
    Hancock, Dana B.
    Bierut, Laura J.
    Spitz, Margaret R.
    Gaddis, Nathan C.
    Lutz, Sharon M.
    Gu, Fangyi
    Johnson, Eric O.
    Kamal, Ahsan
    Pikielny, Claudio
    Zhu, Dakai
    Lindström, Sara
    Jiang, Xia
    Tyndale, Rachel F.
    Chenevix-Trench, Georgia
    Beesley, Jonathan
    Bossé, Yohan
    Chanock, Stephen
    Brennan, Paul
    Landi, Maria Teresa
    Amos, Christopher I.
    Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 7, p. 1126-1132Article in journal (Refereed)
    Abstract [en]

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  • 42. Miletic, Hrvoje
    et al.
    Niclou, Simone P
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. NorLux Neuro-Oncology Laboratory, CRP-Santé, Luxembourg.
    Bjerkvig, Rolf
    Anti-VEGF therapies for malignant glioma: treatment effects and escape mechanisms2009In: Expert opinion on therapeutic targets, ISSN 1472-8222, E-ISSN 1744-7631, Vol. 13, no 4, p. 455-468Article, review/survey (Refereed)
    Abstract [en]

    Background: Glioblastoma multiforme (GBM) has a very poor prognosis and novel treatment strategies are urgently needed. GBM appears to be an optimal target for anti-angiogenic therapy as the tumour shows a high degree of endothelial cell proliferation and pro-angiogenic growth factor expression. Objective: To examine the role of angiogenic factors (particularly VEGF) in glioma and whether inhibition of these factors can be used as a treatment.

    Methods: A review of relevant literature.

    Results/conclusions: Anti-angiogenic therapy has fulfilled the proof of concept in glioma animal models. In glioma patients, the efficacy of anti-angiogenic mono-therapies initially has been disappointing. However recent clinical trials combining bevacizumab, an anti-VEGF antibody, with chemotherapy reported very encouraging response rates. Although randomized phase III clinical trials with anti-angiogenic molecules are not yet available for GBM patients, this treatment regimen is already applied off protocol in several clinical centers. It should be kept in mind though that tumours can develop escape mechanisms. In particular invasive cells, which migrate away from the highly vascularized tumour core, are not targeted by anti-angiogenic therapies. In our opinion, the future of anti-angiogenic therapy will rely on a combination strategy including chemotherapy and drugs that target invasive glioma cells.

  • 43. Muller, David C.
    et al.
    Larose, Tricia L.
    Hodge, Allison
    Guida, Florence
    Langhammer, Arnulf
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Meyer, Klaus
    Cai, Qiuyin
    Arslan, Alan A.
    Zeleniuch-Jacquotte, Anne
    Albanes, Demetrius
    Giles, Graham G.
    Sesso, Howard D.
    Lee, I-Min
    Gaziano, J. Michael
    Yuan, Jian-Min
    Bolton, Judith Hoffman
    Buring, Julie E.
    Visvanathan, Kala
    Le Marchand, Loic
    Purdue, Mark P.
    Caporaso, Neil E.
    Midttun, Oivind
    Ueland, Per M.
    Prentice, Ross L.
    Weinstein, Stephanie J.
    Stevens, Victoria L.
    Zheng, Wei
    Blot, William J.
    Shu, Xiao-Ou
    Zhang, Xuehong
    Xiang, Yong-Bing
    Koh, Woon-Puay
    Hveem, Kristian
    Thomson, Cynthia A.
    Pettinger, Mary
    Engstrom, Gunnar
    Brunnstrom, Hans
    Milne, Roger L.
    Stampfer, Meir J.
    Han, Jiali
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Brennan, Paul
    Severi, Gianluca
    Johansson, Mattias
    Circulating high sensitivity C reactive protein concentrations and risk of lung cancer: nested case-control study within Lung Cancer Cohort Consortium2019In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 364, article id k4981Article in journal (Refereed)
    Abstract [en]

    Objectives To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.

    Design Nested case-control study.

    Setting 20 population based cohort studies in Asia, Europe, Australia, and the United States.

    Participants 5299 patients with incident lung cancer, with individually incidence density matched controls.

    Exposure Circulating hsCRP concentrations in prediagnostic serum or plasma samples.

    Main outcome measure Incident lung cancer diagnosis.

    Results A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.

    Conclusions Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.

  • 44.
    Mörén, Lina
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information2015In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 5, no 3, p. 502-520Article in journal (Refereed)
    Abstract [en]

    Glioma grading and classification, today based on histological features, is not always easy to interpret and diagnosis partly relies on the personal experience of the neuropathologists. The most important feature of the classification is the aimed correlation between tumor grade and prognosis. However, in the clinical reality, large variations exist in the survival of patients concerning both glioblastomas and low-grade gliomas. Thus, there is a need for biomarkers for a more reliable classification of glioma tumors as well as for prognosis. We analyzed relative metabolite concentrations in serum samples from 96 fasting glioma patients and 81 corresponding tumor samples with different diagnosis (glioblastoma, oligodendroglioma) and grade (World Health Organization (WHO) grade II, III and IV) using gas chromatography-time of flight mass spectrometry (GC-TOFMS). The acquired data was analyzed and evaluated by pattern recognition based on chemometric bioinformatics tools. We detected feature patterns in the metabolomics data in both tumor and serum that distinguished glioblastomas from oligodendrogliomas (p(tumor) = 2.46 × 10(-8), p(serum) = 1.3 × 10(-5)) and oligodendroglioma grade II from oligodendroglioma grade III (p(tumor) = 0.01, p(serum) = 0.0008). Interestingly, we also found patterns in both tumor and serum with individual metabolite features that were both elevated and decreased in patients that lived long after being diagnosed with glioblastoma compared to those who died shortly after diagnosis (p(tum)(o)(r) = 0.006, p(serum) = 0.004; AUROCC(tumor) = 0.846 (0.647-1.000), AUROCC(serum) = 0.958 (0.870-1.000)). Metabolic patterns could also distinguish long and short survival in patients diagnosed with oligodendroglioma (p(tumor) = 0.01, p(serum) = 0.001; AUROCC(tumor) = 1 (1.000-1.000), AUROCC(serum) = 1 (1.000-1.000)). In summary, we found different metabolic feature patterns in tumor tissue and serum for glioma diagnosis, grade and survival, which indicates that, following further verification, metabolomic profiling of glioma tissue as well as serum may be a valuable tool in the search for latent biomarkers for future characterization of malignant glioma.

  • 45.
    Mörén, Lina
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Metabolomic profiling of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl. 6, p. 96-96, article id OM-24Article in journal (Other academic)
    Abstract [en]

    High-grade glioma is the most common brain tumor in adults, and the prognosis for patients diagnosed with this type of cancer is still poor. The biological behavior of the tumors is correlated to the classification and the World Health Organization (WHO) grading system, in which the grading reflects the increased aggressiveness. The classification system has been developed and improved over the years, but there are still problems with possible clinical implications. The histological features are not always easy to interpret, and diagnosis relies partly on personal experience of the neuropathologist. The most important component in the classification is the correlation between tumor grade and prognosis; however, the clinical reality shows a large variation in the survival of patients with glioblastomas and low-grade gliomas. Thus, there is a need for biomarkers to obtain a more reliable classification of glioma tumors and also prognostic markers. We have performed a metabolomic profiling study of 81 tissue samples and 96 corresponding serum samples from patients with different glioma diagnoses (glioblastoma or oligodendroglioma) and grades (WHO grades II, IIIs and IV). The samples were analyzed by a global screening strategy using gas chromatography/time of flight mass spectrometry (GC/TOFMS). The acquired data were analyzed and evaluated by chemometrics-based bioinformatics methods in search for metabolite patterns of clinical relevance. We found metabolite patterns in both tissue and serum that distinguished glioblastomas from oligodendrogliomas and oligodendroglioma grade II from oligodendroglioma grade III. Interestingly, we also found metabolites elevated (eg, glycerol-3-phoshate, myo-inositol, ribitol, and fructose) and decreased (eg, octadecanoic acid and maltose) in glioblastoma patients that were associated with long survival (>3 years). Metabolite patterns associated with survival were also found in patients diagnosed with oligodendroglioma. These findings indicate that metabolomic profiling of glioma tissue and serum may be a valuable tool in future characterization of malignant glioma.

  • 46.
    Mörén, Lina
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wibom, Carl
    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.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas2016In: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 11, article id 51Article in journal (Refereed)
    Abstract [en]

    Background: Glioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for supplementary biomarkers that could provide reliable and early assessment of treatment efficacy. Analysis of alterations in the metabolome may be a source for identification of new biomarker patterns harboring predictive information. Ideally, the biomarkers should be found within an easily accessible compartment such as the blood. Method: Using gas-chromatographic-time-of-flight-mass spectroscopy we have analyzed serum samples from 11 patients with glioblastoma during the initial phase of radiotherapy. Fasting serum samples were collected at admittance, on the same day as, but before first treatment and in the morning after the second and fifth dose of radiation. The acquired data was analyzed and evaluated by chemometrics based bioinformatics methods. Our findings were compared and discussed in relation to previous data from microdialysis in tumor tissue, i.e. the extracellular compartment, from the same patients. Results: We found a significant change in metabolite pattern in serum comparing samples taken before radiotherapy to samples taken during early radiotherapy. In all, 68 metabolites were lowered in concentration following treatment while 16 metabolites were elevated in concentration. All detected and identified amino acids and fatty acids together with myo-inositol, creatinine, and urea were among the metabolites that decreased in concentration during treatment, while citric acid was among the metabolites that increased in concentration. Furthermore, when comparing results from the serum analysis with findings in tumor extracellular fluid we found a common change in metabolite patterns in both compartments on an individual patient level. On an individual metabolite level similar changes in ornithine, tyrosine and urea were detected. However, in serum, glutamine and glutamate were lowered after treatment while being elevated in the tumor extracellular fluid. Conclusion: Cross-validated multivariate statistical models verified that the serum metabolome was significantly changed in relation to radiation in a similar pattern to earlier findings in tumor tissue. However, all individual changes in tissue did not translate into changes in serum. Our study indicates that serum metabolomics could be of value to investigate as a potential marker for assessing early response to radiotherapy in malignant glioma.

  • 47. Nilsson, Per
    et al.
    Ceberg, Crister
    Kjellén, Elisabeth
    Gagliardi, Giovanna
    Blomgren, Klas
    Nilsson, Sten
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Glimelius, Bengt
    A template for writing radiotherapy protocols2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 2, p. 275-279Article in journal (Refereed)
    Abstract [en]

    Background: Well-specified and unambiguous treatment protocols are essential both for current practice and for the future development of radiation therapy. In order to provide assistance for writing good protocols, irrespective of treatment intention and complexity, up-to-date guidelines are highly desirable. Methods: We have analysed the radiotherapy work-flow, including clinical and physical aspects, such as preparatory imaging, treatment planning, delivery and evaluation, with the aim to outline a consistent framework covering the entire radiotherapy process. Results: Based on the analysis, a recipe-style template for specifying the description of the radiotherapy process has been designed. The template is written in a general format, which allows for modified phrasing, and should be customised for the specific clinical situation and diagnosis, as well as facility resources. Conclusions: The template can be used as a tool to ensure a consistent and comprehensive description of the radiotherapy section of clinical guidelines, care programmes and clinical trial protocols.

  • 48. Nyman, J.
    et al.
    Bergström, S.
    Björkestrand, H.
    Svärd, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ekman, S.
    Lundin, E.
    Holmberg, E.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Friesland, S.
    Hallqvist, A.
    Dose Escalated Chemo-RT to 84 Gy in Stage III NSCLC Appears Excessively Toxic: Results from a Randomized Phase II Trial2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 10, p. S373-S373Article in journal (Other academic)
    Abstract [en]

    Background: Concurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease, however, with a rather high probability of locoregional and metastatic recurrence further treatment optimization is warranted. Based on previous one-armed trials with dose escalated radiotherapy, showing feasibility, the Swedish Lung Cancer Study Group aimed to investigate whether dose escalation based on individual normal tissue constraints could improve outcome in this randomized phase II trial.

    Method: NSCLC patients with stage III disease, good performance status (0-1), adequate lung function (FEV1 > 1.0 L and CO diff. > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. The radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to a total dose of 68 Gy (standard arm 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 while keeping the total treatment time constant at seven weeks with the same dose to involved nodes and primary tumor.

    Result: 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 the dose escalated group compared to 28 and 45 months in the standard group. The 1-, 3- and 5-year survival rates were 56%, 33% and 17% in the escalated arm and 72%, 61% and 34% in the standard arm. There were four toxicity-related deaths due to esophageal perforations (one in arm A and three in arm B) and three deaths due to pneumonitis (one in arm A and two in arm B).

    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 5-year survival of 34%. A possible step forward will be to improve systemic therapy, but future approaches with escalated radiotherapy may include boost techniques to remaining PET positive areas or different escalation schedules to the primary tumor and mediastinal nodes.

  • 49. Rosenberger, Albert
    et al.
    Hung, Rayjean J.
    Christiani, David C.
    Caporaso, Neil E.
    Liu, Geoffrey
    Bojesen, Stig E.
    Le Marchand, Loic
    Haiman, Ch. A.
    Albanes, Demetrios
    Aldrich, Melinda C.
    Tardon, Adonina
    Fernandez-Tardon, G.
    Rennert, Gad
    Field, John K.
    Kiemeney, B.
    Lazarus, Philip
    Haugen, Aage
    Zienolddiny, Shanbeh
    Lam, Stephen
    Schabath, Matthew B.
    Andrew, Angeline S.
    Brunnsstom, Hans
    Goodman, Gary E.
    Doherty, Jennifer A.
    Chen, Chu
    Teare, M. Dawn
    Wichmann, H. -Erich
    Manz, Judith
    Risch, Angela
    Muley, Thomas R.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Brennan, Paul
    Landi, Maria Teresa
    Amos, Christopher I.
    Pesch, Beate
    Johnen, Georg
    Bruening, Thomas
    Bickeboeller, Heike
    Gomolka, Maria
    Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners2018In: International Archives of Occupational and Environmental Health, ISSN 0340-0131, E-ISSN 1432-1246, Vol. 91, no 8, p. 937-950Article in journal (Refereed)
    Abstract [en]

    Purpose: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon.

    Methods: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes.

    Results: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11–0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10−6), 5q23.2 (p = 2.5 × 10−6), 1q21.3 (p = 3.2 × 10−6), 10p13 (p = 1.3 × 10−5) and 12p12.1 (p = 7.1 × 10−5). Genes belonging to the Gene Ontology term “DNA dealkylation involved in DNA repair” (GO:0006307; p = 0.0139) or the gene family HGNC:476 “microRNAs” (p = 0.0159) were enriched with LD-blockwise significance.

    Conclusion: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

  • 50. Salomonsson, A.
    et al.
    Patthey, Annika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Reuterswärd, C.
    Jönsson, M.
    Botling, J.
    Brunnström, H.
    Hussein, A.
    Monsef, N.
    Ortiz-Villalon, C.
    Bergman, B.
    De Petris, L.
    Lamberg, K.
    Vikström, A.
    Wagenius, G.
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Brandén, E.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Koyi, H.
    Staaf, J.
    Planck, M.
    A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer2018In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 10, p. S431-S432Article in journal (Other academic)
    Abstract [en]

    Background: Smoking is by far the most important cause of lung cancer. However, lung cancer among never-smokers is common and increasing [1]. A smoking-independent subgroup of lung adenocarcinoma with certain molecular and clinical features exists [2-3]. Therefore, as 1st project within the Swedish Molecular Initiative against Lung cancer (SMIL) we aim to characterize never-smoking lung cancer for etiological, diagnostic and therapeutic purposes.

    Method: Through the Swedish National Lung Cancer Registry [1], we identified all individuals who underwent surgery for lung cancer in Sweden 2005-2014 and who were registered as never-smokers (n=540). At each study site (n=6), clinical data were reviewed by a thoracic oncologist/pulmonologist through patients' medical charts and archived tumor tissues were retrieved and reviewed by a thoracic pathologist. For subsequent studies, we extracted DNA and RNA (using the Qiagen AllPrep kit for FFPE tissue) and constructed tissue microarrays. As a first pre-planned analysis, we performed fusion gene mapping using an RNA-based NanoString nCounter Elements assay, as previously described [4].

    Result: In the first 212 (out of 540) analyzed samples, we detected 17 fusions involving ALK, 8 involving RET, and 2 involving NRG1. In addition, MET exon 14 skipping was found in 17 samples. In total, these findings involved 21% of analyzed cases. Additional results from further studies on the cohort will be presented.

    Conclusion: SMIL is an ongoing nation-wide molecular research collaboration on lung cancer where we currently collect one of the largest never-smoking lung tumor cohorts worldwide. From the first pre-planned analyses, we conclude that, in a population-based cohort of early stage lung cancer from never-smokers, druggable oncogenic fusions are frequent.

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