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  • 1. Agborsangaya, Calypse
    et al.
    Toriola, Adetunji T
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Surcel, Heljia-Marja
    Holl, Katsiaryna
    Parkkila, Seppo
    Tuohimaa, Pentti
    Lukanova, Annekatrin
    Lehtinen, Matti
    The effects of storage time and sampling season on the stability of serum 25-hydroxy vitamin D and androstenedione2010In: Nutrition and Cancer, ISSN 0163-5581, E-ISSN 1532-7914, Vol. 62, no 1, p. 51-57Article in journal (Refereed)
    Abstract [en]

    Knowledge of the stability of serum samples stored in large biobanks is pivotal for reliable assessment of hormone-dependent disease risks. We studied the effects of sample storage time and season of serum sampling on the stability of 25-hydroxy vitamin D (25-OHD) and androstenedione in a stratified random sample of 402 women, using paired sera from the Finnish Maternity Cohort. Serum samples selected were donated between 6 and 24 yr ago. The storage time did not affect serum 25-OHD and androstenedione levels. However, there was a significant mean difference in the 25-OHD levels of sera withdrawn during winter (first sample) vs. during summer (second sample; -18.4 nmol/l, P ≤ 0.001). Also at the individual level, there were significant differences in average 25-OHD levels between individuals with the paired sera taken at winter–winter compared with other alternatives (summer–winter, winter–summer, and summer–summer). The androstenedione levels showed no such differences. Long-term storage does not affect serum 25-OHD and androstenedione levels, but sampling season is an important determinant of 25-OHD levels. Stored serum samples can be used to study disease associations with both hormones. However, sampling season needs to be taken into account for 25-OHD by considering matching and stratification and, if possible, serial sampling.

  • 2.
    Alamdari, Farhood Iranparvar
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Angiogenesis and other markers for prediction of survival in metastatic renal cell carcinoma.2007In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, no 1, p. 5-9Article in journal (Refereed)
  • 3.
    Andersson, Britta
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Behnam Motlagh, Parviz
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Pharmacological modulation of lung cancer cells for potassium ion depletion2005In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, no 4, p. 2609-2616Article in journal (Refereed)
  • 4.
    Andersson, Britta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Janson, Veronica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Behnam Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Onkologi.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells.2006In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 20, no 6, p. 986-994Article in journal (Refereed)
  • 5.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation2002In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 19, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

  • 6. Baglietto, Laura
    et al.
    Ponzi, Erica
    Haycock, Philip
    Hodge, Allison
    Bianca Assumma, Manuela
    Jung, Chol-Hee
    Chung, Jessica
    Fasanelli, Francesca
    Guida, Florence
    Campanella, Gianluca
    Chadeau-Hyam, Marc
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ala, Ugo
    Provero, Paolo
    Wong, Ee Ming
    Joo, Jihoon
    English, Dallas R
    Kazmi, Nabila
    Lund, Eiliv
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    Barrdahl, Myrto
    Sandanger, Torkjel M
    Southey, Melissa C
    Giles, Graham G
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Vineis, Paolo
    Polidoro, Silvia
    Relton, Caroline L
    Severi, Gianluca
    DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 1, p. 50-61Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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  • 8.
    Behnam Motlagh, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brännstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Co-expression of Globotriasosylceramide (Gb3) With MDR1 in Cisplatin-resistant Pleural Mesothelioma and Non-small Cell Lung Cancer Cell May Lead to a New Tumour Resistance Treatment Approach2011Conference paper (Refereed)
  • 9.
    Behnam-Mothlag, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karlsson, Terese
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Cisplatin Resistance in Malignant Pleural Mesothelioma2012In: Mesotheliomas: Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnosis, Treatment, Prognosis / [ed] Alexander Zubritsky, Zagreb: InTech, 2012, Vol. 11, p. 169-186Chapter in book (Refereed)
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  • 10.
    Behnam-Motlagh, Parviz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Tyler, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Verotoxin-1 Treatment or Manipulation of its Receptor Globotriaosylceramide (Gb3) for Reversal of Multidrug Resistance to Cancer Chemotherapy2010In: Toxins, ISSN 2072-6651, Vol. 2, no 10, p. 2467-2477Article, review/survey (Refereed)
    Abstract [en]

    A major problem with anti-cancer drug treatment is the development of acquired multidrug resistance (MDR) of the tumor cells. Verotoxin-1 (VT-1) exerts its cytotoxicity by targeting the globotriaosylceramide membrane receptor (Gb3), a glycolipid associated with multidrug resistance. Gb3 is overexpressed in many human tumors and tumor cell lines with inherent or acquired MDR. Gb3 is co-expressed and interplays with the membrane efflux transporter P-gp encoded by the MDR1 gene. P-gp could act as a lipid flippase and stimulate Gb3 induction when tumor cells are exposed to cancer chemotherapy. Recent work has shown that apoptosis and inherent or acquired multidrug resistance in Gb3-expressing tumors could be affected by VT-1 holotoxin, a sub-toxic concentration of the holotoxin concomitant with chemotherapy or its Gb3-binding B-subunit coupled to cytotoxic or immunomodulatory drug, as well as chemical manipulation of Gb3 expression. The interplay between Gb3 and P-gp thus gives a possible physiological approach to augment the chemotherapeutic effect in multidrug resistant tumors.

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  • 11. Berggrund, Malin
    et al.
    Enroth, Stefan
    Lundberg, Martin
    Assarsson, Erika
    Stålberg, Karin
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Olovsson, Matts
    Gyllensten, Ulf
    Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay2019In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 4, p. 735-743, article id RA118.001208Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared to controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared to population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

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

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

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

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

  • 14.
    Byun, Jinyoung
    et al.
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Han, Younghun
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Li, Yafang
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Xia, Jun
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States.
    Long, Erping
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Choi, Jiyeon
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Xiao, Xiangjun
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States.
    Zhu, Meng
    Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
    Zhou, Wen
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States.
    Sun, Ryan
    Department of Biostatistics, University of Texas, M.D. Anderson Cancer Center, TX, Houston, United States.
    Bossé, Yohan
    Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval, Department of Molecular Medicine, Laval University, QC, Quebec City, Canada.
    Song, Zhuoyi
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States.
    Schwartz, Ann
    Department of Oncology, Wayne State University School of Medicine, MI, Detroit, United States; Karmanos Cancer Institute, MI, Detroit, United States.
    Lusk, Christine
    Department of Oncology, Wayne State University School of Medicine, MI, Detroit, United States; Karmanos Cancer Institute, MI, Detroit, United States.
    Rafnar, Thorunn
    deCODE genetics/Amgen Sturlugata 8, Reykjavik, Iceland.
    Stefansson, Kari
    deCODE genetics/Amgen Sturlugata 8, Reykjavik, Iceland.
    Zhang, Tongwu
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Zhao, Wei
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Pettit, Rowland W.
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States.
    Liu, Yanhong
    Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Li, Xihao
    Department of Biostatistics, Harvard TH Chan School of Public Health, MA, Boston, United States.
    Zhou, Hufeng
    Department of Biostatistics, Harvard TH Chan School of Public Health, MA, Boston, United States.
    Walsh, Kyle M.
    Duke Cancer Institute, Duke University Medical Center, NC, Durham, United States.
    Gorlov, Ivan
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Gorlova, Olga
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Zhu, Dakai
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Rosenberg, Susan M.
    Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, TX, Houston, United States.
    Pinney, Susan
    University of Cincinnati College of Medicine, OH, Cincinnati, United States.
    Bailey-Wilson, Joan E.
    National Human Genome Research Institute, NIH, MD, Baltimore, United States.
    Mandal, Diptasri
    Louisiana State University Health Sciences Center, LA, New Orleans, United States.
    de Andrade, Mariza
    Mayo Clinic, College of Medicine, MN, Rochester, United States.
    Gaba, Colette
    The University of Toledo College of Medicine and Life Sciences, University of Toledo, OH, Toledo, United States.
    Willey, James C.
    The University of Toledo College of Medicine and Life Sciences, University of Toledo, OH, Toledo, United States.
    You, Ming
    Center for Cancer Prevention, Houston Methodist Research Institute, TX, Houston, United States.
    Anderson, Marshall
    University of Cincinnati College of Medicine, OH, Cincinnati, United States.
    Wiencke, John K.
    Department of Neurological Surgery, University of California, San Francisco, CA, San Francisco, United States.
    Albanes, Demetrius
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Lam, Stephan
    Department of Integrative Oncology, BC Cancer, BC, Vancouver, Canada.
    Tardon, Adonina
    Public Health Department, University of Oviedo, ISPA and CIBERESP, Asturias, Spain.
    Chen, Chu
    Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Goodman, Gary
    Swedish Cancer Institute, WA, Seattle, United States.
    Bojeson, Stig
    Department of Clinical Biochemistry, Herlev Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Brenner, Hermann
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Landi, Maria Teresa
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Chanock, Stephen J.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Muley, Thomas
    Division of Cancer Epigenomics, DKFZ – German Cancer Research Center, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany.
    Risch, Angela
    Division of Cancer Epigenomics, DKFZ – German Cancer Research Center, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany; Department of Biosciences and Medical Biology, Allergy-Cancer-BioNano Research Centre, University of Salzburg, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria.
    Wichmann, H.-Erich
    Institute of Epidemiology, Helmholtz Center, Munich, Germany.
    Bickeböller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
    Christiani, David C.
    Department of Epidemiology, Harvard T.H.Chan School of Public Health, MA, Boston, United States.
    Rennert, Gad
    Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    Arnold, Susanne
    University of Kentucky, Markey Cancer Center, KY, Lexington, United States.
    Field, John K.
    Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay
    Department of Biostatistics, University of Texas, M.D. Anderson Cancer Center, TX, Houston, United States; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, TX, Houston, United States.
    Le Marchand, Loic
    Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States.
    Melander, Olle
    Faculty of Medicine, Lund University, Lund, Sweden.
    Brunnstrom, Hans
    Faculty of Medicine, Lund University, Lund, Sweden.
    Liu, Geoffrey
    University Health Network- The Princess Margaret Cancer Centre, Ontario, Toronto, Canada.
    Andrew, Angeline S.
    Departments of Epidemiology and Community and Family Medicine, Dartmouth College, NH, Hanover, United States.
    Kiemeney, Lambertus A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Shen, Hongbing
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Zienolddiny, Shanbeh
    National Institute of Occupational Health, Oslo, Norway.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Caporaso, Neil
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Cox, Angela
    Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
    Hong, Yun-Chul
    Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    Yuan, Jian-Min
    UPMC Hillman Cancer Center and Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, Pittsburgh, United States.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, WA, Spokane, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, FL, Tampa, United States.
    Aldrich, Melinda C.
    Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Patel, Alpa
    American Cancer Society, GA, Atlanta, United States.
    Lan, Qing
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Rothman, Nathaniel
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Taylor, Fiona
    Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.
    Kachuri, Linda
    Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, San Francisco, United States.
    Witte, John S.
    Department of Epidemiology and Population Health, Stanford University, CA, Stanford, United States.
    Sakoda, Lori C.
    Division of Research, Kaiser Permanente Northern California, CA, Oakland, United States.
    Spitz, Margaret
    Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States.
    Brennan, Paul
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Lin, Xihong
    Department of Biostatistics, Harvard TH Chan School of Public Health, MA, Boston, United States.
    McKay, James
    Section of Genetics, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Hung, Rayjean J.
    Lunenfeld-Tanenbaum Research Institute, Sinai Health System, ON, Toronto, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, ON, Toronto, Canada.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor College of Medicine, TX, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, TX, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, TX, Houston, United States.
    Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer2022In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 54, no 8, p. 1167-1177Article in journal (Refereed)
    Abstract [en]

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

  • 15.
    Bölenius, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Brulin, Christine
    Umeå University, Faculty of Medicine, Department of Nursing.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Söderberg, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    A content validated questionnaire for assessment of self reported venous blood sampling practices2012In: BMC Research Notes, E-ISSN 1756-0500, Vol. 5, p. 39-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Venous blood sampling is a common procedure in health care. It is strictly regulated by national and international guidelines. Deviations from guidelines due to human mistakes can cause patient harm. Validated questionnaires for health care personnel can be used to assess preventable "near misses"--i.e. potential errors and nonconformities during venous blood sampling practices that could transform into adverse events. However, no validated questionnaire that assesses nonconformities in venous blood sampling has previously been presented. The aim was to test a recently developed questionnaire in self reported venous blood sampling practices for validity and reliability.

    FINDINGS: We developed a questionnaire to assess deviations from best practices during venous blood sampling. The questionnaire contained questions about patient identification, test request management, test tube labeling, test tube handling, information search procedures and frequencies of error reporting. For content validity, the questionnaire was confirmed by experts on questionnaires and venous blood sampling. For reliability, test-retest statistics were used on the questionnaire answered twice. The final venous blood sampling questionnaire included 19 questions out of which 9 had in total 34 underlying items. It was found to have content validity. The test-retest analysis demonstrated that the items were generally stable. In total, 82% of the items fulfilled the reliability acceptance criteria.

    CONCLUSIONS: The questionnaire could be used for assessment of "near miss" practices that could jeopardize patient safety and gives several benefits instead of assessing rare adverse events only. The higher frequencies of "near miss" practices allows for quantitative analysis of the effect of corrective interventions and to benchmark preanalytical quality not only at the laboratory/hospital level but also at the health care unit/hospital ward.

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  • 16.
    Bölenius, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Brulin, Christine
    Umeå University, Faculty of Medicine, Department of Nursing.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Karin
    Umeå University, Faculty of Medicine, Department of Nursing. Institutionen för omvårdnad i Örnsköldsvik.
    Söderberg, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Impact of a large-scale educational intervention program on venous blood specimen collection practices2013In: BMC Health Services Research, E-ISSN 1472-6963, Vol. 13, article id 463Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Phlebotomy performed with poor adherence to venous blood specimen collection (VBSC) guidelines jeopardizes patient safety and may lead to patient suffering and adverse events. A first questionnaire study demonstrated low compliance to VBSC guidelines, motivating an educational intervention of all phlebotomists within a county council. The aim was to evaluate the impact of a large-scale educational intervention program (EIP) on primary health care phlebotomists' adherence to VBSC guidelines. We hypothesised that the EIP would improve phlebotomists' VBSC practical performance.

    METHODS: The present study comprise primary health care centres (n = 61) from two county councils in northern Sweden. The final selected study group consisted of phlebotomists divided into an intervention group (n = 84) and a corresponding control group (n = 79). Both groups responded to a validated self-reported VBSC questionnaire twice. The EIP included three parts: guideline studies, an oral presentation, and an examination. Non-parametric statistics were used for comparison within and between the groups.

    RESULTS: Evaluating the EIP, we found significant improvements in the intervention group compared to the control group on self-reported questionnaire responses regarding information search (ES = 0.23-0.33, p < 0.001-0.003), and patient rest prior to phlebotomy (ES = 0.27, p = 0.004). Test request management, patient identity control, release of venous stasis, and test tube labelling had significantly improved in the intervention group but did not significantly differ from the control group (ES = 0.22- 0.49, p = < 0.001- 0.006). The control group showed no significant improvements at all (ES = 0--0.39, p = 0.016-0.961).

    CONCLUSIONS: The present study demonstrated several significant improvements on phlebotomists' adherence to VBSC practices. Still, guideline adherence improvement to several crucial phlebotomy practices is needed. We cannot conclude that the improvements are solely due to the EIP and suggest future efforts to improve VBSC. The program should provide time for reflections and discussions. Furthermore, a modular structure would allow directed educational intervention based on the specific VBSC guideline flaws existing at a specific unit. Such an approach is probably more effective at improving and sustaining adherence to VBSC guidelines than an EIP containing general pre-analytical practices.

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  • 17.
    Bölenius, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Söderberg, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Brulin, Christine
    Umeå University, Faculty of Medicine, Department of Nursing.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Minor improvement of venous blood specimen collection practices in primary health care after a large-scale educational intervention2013In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 51, no 2, p. 303-310Article in journal (Refereed)
    Abstract [en]

    Background: Venous blood specimen collection is a common health care practice that has to follow strict guidelines, non-compliance among sampling staff may compromise patient safety. We evaluated a large-scale 2 h educational intervention that emphasised guideline adherence to assess possible improvements of venous blood specimen collection practices.

    Methods: Blood specimen haemolysis is usually caused by inadequate venous blood specimen collection and handling, reflecting overall pre-analytical handling. We monitored haemolysis of serum samples with haemolysis index corresponding to ≥150 mg/L of free haemoglobin for specimens sent from 11 primary health care centres and analysed on a Vitros 5,1 clinical chemistry analyser before (2008, n=6652 samples) and after (2010, n=6121 samples) the intervention.

    Results: The total percentage of haemolysed specimens was 11.8% compared to 10.5% (p=0.022) before the intervention. As groups, rural primary health care centres demonstrated a significant reduction [Odds ratios (OR)=0.744] of haemolysed specimens after intervention, whereas urban primary health care centres demonstrated a significant increase (OR=1.451) of haemolysis.

    Conclusions: A large-scale 2 h educational intervention to make venous blood specimen collection staff comply with guideline practices had minor effects on collection practices. Educational interventions may be effective in wards/care centres demonstrating venous blood specimen collection practices with larger deviations from guidelines.

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  • 18. Cadamuro, Janne
    et al.
    Lippi, Giuseppe
    von Meyer, Alexander
    Ibarz, Mercedes
    van Dongen-Lases, Edmee
    Cornes, Michael
    Nybo, Mads
    Vermeersch, Pieter
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Guimaraes, Joao Tiago
    Kristensen, Gunn B. B.
    de la Salle, Barbara
    Simundic, Ana-Maria
    European survey on preanalytical sample handling - Part 1: How do European laboratories monitor the preanalytical phase? On behalf of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE)2019In: Biochemia Medica, ISSN 1330-0962, E-ISSN 1846-7482, Vol. 29, no 2, article id 020704Article in journal (Refereed)
    Abstract [en]

    Introduction: Compared to other activities of the testing process, the preanalytical phase is plagued by a lower degree of standardization, which makes it more vulnerable to errors. With the aim of providing guidelines and recommendations, the EFLM WG-PRE issued a survey across European medical laboratories, to gather information on local preanalytical practices. This is part one of two coherent articles, which covers all practices on monitoring preanalytical quality except haemolysis, icterus and lipemia (HIL).

    Materials and methods: An online survey, containing 39 questions dealing with a broad spectrum of preanalytical issues, was disseminated to EFLM member countries. The survey included questions on willingness of laboratories to engage in preanalytical issues.

    Results: Overall, 1405 valid responses were received from 37 countries. 1265 (94%) responders declared to monitor preanalytical errors. Assessment, documentation and further use of this information varied widely among respondents and partially among countries. Many responders were interested in a preanalytical online platform, holding information on various aspects of the preanalytical phase (N = 1177; 87%), in a guideline for measurement and evaluation of preanalytical variables (N = 1235; 92%), and in preanalytical e-learning programs or webinars (N = 1125; 84%). Fewer responders were interested in, or already participating in, preanalytical EQA programs (N = 951; 71%).

    Conclusion: Although substantial heterogeneity was found across European laboratories on preanalytical phase monitoring, the interest in preanalytical issues was high. A large majority of participants indicated an interest in new guidelines regarding preanalytical variables and learning activities. This important data will be used by the WG-PRE for providing recommendations on the most critical issues.

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  • 19. Cadamuro, Janne
    et al.
    Lippi, Giuseppe
    von Meyer, Alexander
    Ibarz, Mercedes
    van Dongen-Lases, Edmee
    Cornes, Michael
    Nybo, Mads
    Vermeersch, Pieter
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Guimaraes, Joao Tiago
    Kristensen, Gunn B. B.
    de la Salle, Barbara
    Simundic, Ana-Maria
    European survey on preanalytical sample handling - Part 2: Practices of European laboratories on monitoring and processing haemolytic, icteric and lipemic samples. On behalf of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE)2019In: Biochemia Medica, ISSN 1330-0962, E-ISSN 1846-7482, Vol. 29, no 2, article id 020705Article in journal (Refereed)
    Abstract [en]

    Introduction: No guideline currently exists on how to detect or document haemolysis, icterus or lipemia (HIL) in blood samples, nor on subsequent use of this information. The EFLM WG-PRE has performed a survey for assessing current practices of European laboratories in HIL monitoring. This second part of two coherent articles is focused on HIL.

    Materials and methods: An online survey, containing 39 questions on preanalytical issues, was disseminated among EFLM member countries. Seventeen questions exclusively focused on assessment, management and follow-up actions of HIL in routine blood samples.

    Results: Overall, 1405 valid responses from 37 countries were received. A total of 1160 (86%) of all responders stating to analyse blood samples - monitored HIL. HIL was mostly checked in clinical chemistry samples and less frequently in those received for coagulation, therapeutic drug monitoring and serology/infectious disease testing. HIL detection by automatic HIL indices or visual inspection, along with haemolysis cut-offs definition, varied widely among responders. A quarter of responders performing automated HIL checks used internal quality controls. In haemolytic/icteric/lipemic samples, most responders (70%) only rejected HIL-sensitive parameters, whilst about 20% released all test results with general comments. Other responders did not analysed but rejected the entire sample, while some released all tests, without comments. Overall, 26% responders who monitored HIL were using this information for monitoring phlebotomy or sample transport quality.

    Conclusion: Strategies for monitoring and treating haemolytic, icteric or lipemic samples are quite heterogeneous in Europe. The WG-PRE will use these insights for developing and providing recommendations aimed at harmonizing strategies across Europe.

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

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

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  • 21. Chen, Tianhui
    et al.
    Lukanova, Annekatrin
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schock, Helena
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    IGF-I during primiparous pregnancy and maternal risk of breast cancer2010In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 121, no 1, p. 169-175Article in journal (Refereed)
    Abstract [en]

    Previously, we reported that insulin-like growth factor (IGF)-I during early pregnancy is positively associated with maternal risk of breast cancer. To further explore this association, we designed a new study limited to women who donated a blood sample during their first pregnancy ending with childbirth. A case-control study was nested within the Northern Sweden Maternity Cohort in which repository since 1975, serum specimens remaining after early pregnancy screening for infectious diseases had been preserved. Study subjects were selected among women who donated a blood sample during the full-term pregnancy that led to the birth of their first child. Two hundred and forty-four women with invasive breast cancer were eligible. Two controls, matching the index case for age and date at blood donation were selected (n = 453). IGF-I was measured in serum samples on an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. A significant positive association of breast cancer with IGF-I was observed, with OR of 1.73 (95% CI: 1.14-2.63) for the top tertile, P < 0.009. Subgroup analyses did not indicate statistical heterogeneity of the association by ages at sampling and diagnosis or by lag time to cancer diagnosis, although somewhat stronger associations with risk were observed in women < or = age 25 at index pregnancy and for cases diagnosed within 15 years of blood donation. The results of the study add further evidence for an adverse effect of elevated IGF-I concentrations during early reproductive life on risk of breast cancer.

  • 22. Chen, Tianhui
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zeleniuch-Jacquotte, Anne
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Afanasyeva, Yelena
    Schock, Helena
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Toniolo, Paolo
    Lukanova, Annekatrin
    Maternal hormones during early pregnancy: a cross-sectional study2010In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 5, p. 719-727Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II. METHODS: About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models. RESULTS: In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed. CONCLUSIONS: Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations.

  • 23. Chen, Tianhui
    et al.
    Surcel, Helja-Marja
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kaasila, Marjo
    Lakso, Hans-Ake
    Schock, Helena
    Kaaks, Rudolf
    Koskela, Pentti
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Pukkala, Eero
    Zeleniuch-Jacquotte, Anne
    Toniolo, Paolo
    Lehtinen, Matti
    Lukanova, Annekatrin
    Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 2, p. 324-336Article in journal (Refereed)
    Abstract [en]

    This is the first prospective study providing initial evidence that elevated androgens play a role in the pathogenesis of SCST. Impact: Our study may note a particular need for larger confirmatory investigations on sex steroids and NEOC. Cancer Epidemiol Biomarkers Prev; 20(2); 324-36. ©2010 AACR.

  • 24.
    Cheng, Chao
    et al.
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Hong, Wei
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States.
    Li, Yafang
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Xiao, Xiangjun
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States.
    McKay, James
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Han, Younghun
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Byun, Jinyoung
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Peng, Bo
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States.
    Albanes, Demetrios
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda, United States.
    Lam, Stephen
    Department of Integrative Oncology, University of British Columbia, BC, Vancouver, Canada.
    Tardon, Adonina
    Public Health Department, University of Oviedo, ISPA and CIBERESP, Asturias, Spain.
    Chen, Chu
    Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Center, WA, Seattle, United States.
    Bojesen, Stig E.
    Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Landi, Maria T.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Maryland, Bethesda, United States.
    Johansson, Mattias
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Risch, Angela
    Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
    Bickeböller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
    Wichmann, H-Erich
    Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich, Germany.
    Christiani, David C.
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, Massachusetts, Boston, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Massachusetts, Boston, United States.
    Rennert, Gad
    Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    Arnold, Susanne
    University of Kentucky, Markey Cancer Center, Kentucky, Lexington, United States.
    Goodman, Gary
    Swedish Cancer Institute, WA, Seattle, United States.
    Field, John K.
    Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Davies, Michael P.A.
    Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay S.
    Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Texas, Houston, United States; Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Texas, Houston, United States.
    Le Marchand, Loic
    Epidemiology Program, University of Hawaii Cancer Center, HI, Honolulu, United States.
    Liu, Geoffrey
    University Health Network- The Princess Margaret Cancer Centre, California, Toronto, United States.
    Hung, Rayjean J.
    Luenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
    Andrew, Angeline S.
    Department of Epidemiology, Dartmouth College, New Hampshire, Hanover, United States; Department of Community and Family Medicine, Dartmouth College, New Hampshire, Hanover, United States.
    Kiemeney, Lambertus A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Zhu, Meng
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Shen, Hongbing
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
    Zienolddiny, Shan
    National Institute of Occupational Health, Oslo, Norway.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Cox, Angela
    Academic Unit of Clinical Oncology University of Sheffield, Weston Park Hospital, Whitham Road, Sheffield, United Kingdom.
    Hong, Yun-Chul
    Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    Yuan, Jian-Min
    University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, PA, Pittsburgh, United States.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, WA, Spokane, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Florida, Tampa, United States.
    Aldrich, Melinda C.
    Department of Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Brennan, Paul
    Section of Genetics, International Agency for Research on Cancer, WHO, Lyon, France.
    Li, Yong
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Gorlova, Olga
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Gorlov, Ivan
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor College of Medicine, Texas, Houston, United States; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Texas, Houston, United States; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas, Houston, United States.
    Mosaic chromosomal alterations are associated with increased lung cancer risk: insight from the INTEGRAL-ILCCO cohort analysis2023In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380Article in journal (Refereed)
    Abstract [en]

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

  • 25. 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.

  • 26. Cornes, Michael
    et al.
    Ibarz, Mercedes
    Ivanov, Helene
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Blood sampling guidelines with focus on patient safety and identification: a review2019In: Diagnosis, ISSN 2194-8011, E-ISSN 2194-802X, Vol. 6, no 1, p. 33-37Article, review/survey (Refereed)
    Abstract [en]

    It has been well documented over recent years that the preanalytical phase is a leading contributor to errors in the total testing process (TTP). There has however been great progress made in recent years due to the exponential growth of working groups specialising in the field. Patient safety is clearly at the forefront of any healthcare system and any reduction in errors at any stage will improve patient safety. Venous blood collection is a key step in the TTP, and here we review the key errors that occur in venous phlebotomy process and summarise the evidence around their significance to patient safety. Recent studies have identified that patient identification and tube labelling are the steps that carry the highest risk with regard to patient safety. Other studies have shown that in 16.1% of cases, patient identification is incorrectly performed and that 56% of patient identification errors are due to poor labelling practice. We recommend that patient identification must be done using open questions and ideally three separate pieces of information. Labelling of the tube or linking the identity of the patient to the tube label electronically must be done in the presence of the patient whether it is before or after sampling. Combined this will minimise any chance of patient misidentification.

  • 27. Cornes, Michael P.
    et al.
    Church, Stephen
    van Dongen-Lases, Edmee
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Guimaraes, Joao T.
    Ibarz, Mercedes
    Kovalevskaya, Svetlana
    Kristensen, Gunn B. B.
    Lippi, Giuseppe
    Nybo, Mads
    Sprongl, Ludek
    Sumarac, Zorica
    Simundic, Ana-Maria
    The role of European Federation of Clinical Chemistry and Laboratory Medicine Working Group for Preanalytical Phase in standardization and harmonization of the preanalytical phase in Europe2016In: Annals of Clinical Biochemistry, ISSN 0004-5632, E-ISSN 1758-1001, Vol. 53, no 5, p. 539-547Article, review/survey (Refereed)
    Abstract [en]

    Patient safety is a leading challenge in healthcare and from the laboratory perspective it is now well established that preanalytical errors are the major contributor to the overall rate of diagnostic and therapeutic errors. To address this, the European Federation of Clinical Chemistry and Laboratory Medicine Working Group for Preanalytical Phase (EFLM WG-PRE) was established to lead in standardization and harmonization of preanalytical policies and practices at a European level. One of the key activities of the WG-PRE is the organization of the biennial EFLM-BD conference on the preanalytical phase to provide a forum for National Societies (NS) to discuss their issues. Since 2012, a year after the first Preanalytical phase conference, there has been a rapid growth in the number of NS with a working group engaged in preanalytical phase activities and there are now at least 19 countries that have one. As a result of discussions with NS at the third conference held in March 2015 five key areas were identified as requiring harmonisation. These were test ordering, sample transport and storage, patient preparation, sampling procedures and management of unsuitable specimens. The article below summarises the work that has and will be done in these areas. The goal of this initiative is to ensure the EFLM WG-PRE produces work that meets the needs of the European laboratory medicine community. Progress made in the identified areas will be updated at the next preanalytical phase conference and show that we have produced guidance that has enhanced standardisation in the preanalytical phase and improved patient safety throughout Europe.

  • 28. Cornes, Michael
    et al.
    van Dongen-Lases, Edmée
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ibarz, Mercedes
    Kristensen, Gunn
    Lippi, Giuseppe
    Nybo, Mads
    Simundic, Ana-Maria
    Order of blood draw: Opinion Paper by the European Federation for Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase (WG-PRE)2017In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 55, no 1, p. 27-31Article in journal (Refereed)
    Abstract [en]

    It has been well reported over recent years that most errors within the total testing process occur in the pre-analytical phase (46%-68.2%), an area that is usually outside of the direct control of the laboratory and which includes sample collection (phlebotomy). National and international (WHO, CLSI) guidelines recommend that the order of draw of blood during phlebotomy should be blood culture/sterile tubes, then plain tubes/gel tubes, then tubes containing additives. This prevents contamination of sample tubes with additives from previous tubes that could cause erroneous results. There have been a number of studies recently looking at whether order of draw remains a problem with modern phlebotomy techniques and materials, or it is an outdated practice followed simply because of historical reasons. In the following article, the European Federation of Clinical Chemistry and Laboratory Medicine Working Group for the Preanalytical Phase (EFLM WG-PRE) provides an overview and summary of the literature with regards to order of draw in venous blood collection. Given the evidence presented in this article, the EFLM WG-PRE herein concludes that a significant frequency of sample contamination does occur if order of draw is not followed during blood collection and when performing venipuncture under less than ideal circumstances, thus putting patient safety at risk. Moreover, given that order of draw is not difficult to follow and knowing that ideal phlebotomy conditions and protocols are not always followed or possible, EFLM WG-PRE supports the continued recommendation of ensuring a correct order of draw for venous blood collection.

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

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

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

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

  • 31. 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.

  • 32.
    Du, Mulong
    et al.
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Xin, Junyi
    Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Jiangsu, Nanjing, China.
    Zheng, Rui
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Yuan, Qianyu
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Wang, Zhihui
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Liu, Hongliang
    Duke Cancer Institute, Duke University Medical Center, NC, Durham, United States; Department of Population Health Sciences, Duke University School of Medicine, NC, Durham, United States.
    Liu, Hanting
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Cai, Guoshuai
    Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, SC, Columbia, United States.
    Albanes, Demetrius
    Division of Cancer Epidemiology and Genetics, NCI, US NIH, MD, Bethesda, United States.
    Lam, Stephen
    British Columbia Cancer Agency, BC, Vancouver, Canada.
    Tardon, Adonina
    Faculty of Medicine, University of Oviedo, ISPA and CIBERESP, Oviedo, Spain.
    Chen, Chu
    Program in Epidemiology, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Bojesen, Stig E.
    Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.
    Landi, Maria Teresa
    Division of Cancer-Epidemiology and Genetics, NCI, US NIH, MD, Bethesda, United States.
    Johansson, Mattias
    International Agency for Research on Cancer, World-Health Organization, Lyon, France.
    Risch, Angela
    University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria; Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany; German Center for Lung Research (DZL), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Bickeboller, Heike
    Department of Genetic Epidemiology, University Medical Center, Georg August University Gottingen, Gottingen, Germany.
    Wichmann, H-Erich
    Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilian University, Munich, Germany; Institute of Epidemiology II, Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany.
    Rennert, Gad
    Clalit National Cancer Control Center, Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel.
    Arnold, Susanne
    Markey Cancer Center, University of Kentucky, KY, Lexington, United States.
    Brennan, Paul
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Field, John K.
    Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
    Shete, Sanjay S.
    Department of Epidemiology, Division of Cancer Prevention and Population Science, The University of Texas, MD Anderson Cancer Center, TX, Houston, United States.
    Le Marchand, Loïc
    Epidemiology Program, University of Hawaii Cancer Center, Hawaii, Honolulu, United States.
    Liu, Geoffrey
    Princess Margaret Cancer Center, University of Toronto, ON, Toronto, Canada.
    Andrew, Angeline S.
    Norris Cotton Cancer Center, Geisel School of Medicine, NH, Hanover, United States.
    Kiemeney, Lambertus A.
    Radboud University Medical Center, Nijmegen, Netherlands.
    Zienolddiny, Shan
    National Institute of Occupational Health, Oslo, Norway.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Department of Radiation Sciences, Umeå, Sweden.
    Caporaso, Neil E.
    Division of Cancer Epidemiology and Genetics, NCI, US-NIH, MD, Bethesda, United States.
    Cox, Angela
    Department of Oncology, University of Sheffield, Sheffield, United Kingdom.
    Hong, Yun-Chul
    Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
    Yuan, Jian-Min
    UPMC Hillman Cancer Center, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, Pittsburgh, United States.
    Schabath, Matthew B.
    Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, FL, Tampa, United States.
    Aldrich, Melinda C.
    Department of Medicine, Vanderbilt University Medical Center, TN, Nashville, United States.
    Wang, Meilin
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Shen, Hongbing
    Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Chen, Feng
    Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Zhang, Zhengdong
    Depart-ment of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China; Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Jiangsu, Nanjing, China.
    Hung, Rayjean J.
    Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, University of Toronto, ON, Toronto, Canada.
    Amos, Christopher I.
    Institute for Clinical and Translational Research, Baylor Medical College, TX, Houston, United States.
    Wei, Qingyi
    Duke Cancer Institute, Duke University Medical Center, NC, Durham, United States; Department of Population Health Sciences, Duke University School of Medicine, NC, Durham, United States.
    Lazarus, Philip
    Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, WA, Spokane, United States.
    Christiani, David C.
    Department of Environmental Health, Harvard T.H. Chan School of Public Health, MA, Boston, United States; Department of Medicine, Massachusetts General Hospital, MA, Boston, United States.
    Cyp2a6 activity and cigarette consumption interact in smoking-related lung cancer susceptibility2024In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 84, no 4, p. 616-625Article in journal (Refereed)
    Abstract [en]

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

  • 33. Enroth, Stefan
    et al.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gyllensten, Ulf
    Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations2016In: EBioMedicine, E-ISSN 2352-3964, Vol. 12, p. 309-314Article in journal (Refereed)
    Abstract [en]

    The quality of clinical biobank samples is crucial to their value for life sciences research. A number of factors related to the collection and storage of samples may affect the biomolecular composition. We have studied the effect of long-time freezer storage, chronological age at sampling, season and month of the year and on the abundance levels of 108 proteins in 380 plasma samples collected from 106 Swedish women. Storage time affected 18 proteins and explained 4.8–34.9% of the observed variance. Chronological age at sample collection after adjustment for storage-time affected 70 proteins and explained 1.1–33.5% of the variance. Seasonal variation had an effect on 15 proteins and month (number of sun hours) affected 36 proteins and explained up to 4.5% of the variance after adjustment for storage-time and age. The results show that freezer storage time and collection date (month and season) exerted similar effect sizes as age on the protein abundance levels. This implies that information on the sample handling history, in particular storage time, should be regarded as equally prominent covariates as age or gender and need to be included in epidemiological studies involving protein levels.

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  • 34. 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.

  • 35. 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.

  • 36.
    Faraz, Mahmood
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tellström, Andreas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Edwinsdotter Ardnor, Christina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Huminiecki, Lukasz
    Tavelin, Björn
    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.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1 gene copy number analysis by ddPCR and correlations to clinical factors in breast cancer2020In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 20, no 1, article id 459Article in journal (Refereed)
    Abstract [en]

    Background: Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) copy number alterations and unbalanced gene recombination events have been reported to occur in breast cancer. Importantly, LRIG1 loss was recently shown to predict early and late relapse in stage I-II breast cancer.

    Methods: We developed droplet digital PCR (ddPCR) assays for the determination of relative LRIG1 copy numbers and used these assays to analyze LRIG1 in twelve healthy individuals, 34 breast tumor samples previously analyzed by fluorescence in situ hybridization (FISH), and 423 breast tumor cytosols.

    Results: Four of the LRIG1/reference gene assays were found to be precise and robust, showing copy number ratios close to 1 (mean, 0.984; standard deviation, +/-0.031) among the healthy control population. The correlation between the ddPCR assays and previous FISH results was low, possibly because of the different normalization strategies used. One in 34 breast tumors (2.9%) showed an unbalanced LRIG1 recombination event. LRIG1 copy number ratios were associated with the breast cancer subtype, steroid receptor status, ERBB2 status, tumor grade, and nodal status. Both LRIG1 loss and gain were associated with unfavorable metastasis-free survival; however, they did not remain significant prognostic factors after adjustment for common risk factors in the Cox regression analysis. Furthermore, LRIG1 loss was not significantly associated with survival in stage I and II cases.

    Conclusions: Although LRIG1 gene aberrations may be important determinants of breast cancer biology, and prognostic markers, the results of this study do not verify an important role for LRIG1 copy number analyses in predicting the risk of relapse in early-stage breast cancer.

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

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

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

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

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  • 39. Fortner, Renee T.
    et al.
    Tolockiene, Egle
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schock, Helena
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kaaks, Rudolf
    Toniolo, Paolo
    Zeleniuch-Jacquotte, Anne
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Early pregnancy sex steroids during primiparous pregnancies and maternal breast cancer: a nested case-control study in the Northern Sweden Maternity Cohort2017In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 19, article id 82Article in journal (Refereed)
    Abstract [en]

    Background: Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones.

    Methods: We conducted a nested case–control study in the Northern Sweden Maternity Cohort (1975–2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression.

    Results: Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (ORlog2: 0.64 (0.41–1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (ORlog2: 1.57 (1.13–2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11–3.16)). None of the investigated hormones were associated with ER–/PR– disease, or with AR+ or AR+/ER+/PR+ disease.

    Conclusions: Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease.

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  • 40. Fortner, Renée T
    et al.
    Schock, Helena
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Surcel, Helja-Marja
    Early pregnancy sex steroids and maternal breast cancer: a nested case-control study2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 23, p. 6958-6967Article in journal (Refereed)
    Abstract [en]

    Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association.

  • 41. Fortner, Renée T
    et al.
    Schock, Helena
    Kaaks, Rudolf
    Lehtinen, Matti
    Pukkala, Eero
    Lakso, Hans-Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Tanner, Minna
    Kallio, Raija
    Joensuu, Heikki
    Korpela, Jaana
    Toriola, Adetunji T
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zeleniuch-Jacquotte, Anne
    Toniolo, Paolo
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Surcel, Heljä-Marja
    Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 1, p. 134-141Article in journal (Refereed)
    Abstract [en]

    Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1, 1.10; 95% CI, 0.64-1.89; ≥15 years, ORQ4 vs. Q1, 1.36; 95% CI, 0.86-2.13; pheterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. 

  • 42. Geoghegan, Fintan
    et al.
    Buckland, Robert J.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rogers, Eric T.
    Khalifa, Karima
    O'Connor, Emma B.
    Rooney, Mary F.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Porter, Richard K.
    Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells2017In: Oncotarget, E-ISSN 1949-2553, Vol. 8, no 55, p. 94711-94725Article in journal (Refereed)
    Abstract [en]

    Acquired cisplatin resistance is a common feature of tumours following cancer treatment with cisplatin and also of non-small cell lung cancer (H1299) and mesothelioma (P31) cell lines exposed to cisplatin. To elucidate the cellular basis of acquired cisplatin resistance, a comprehensive bioenergetic analysis was undertaken. We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance. The differential mitochondrial abundance was supported by data showing reduced sirtuin 1 (SIRT1), peroxisome-proliferator activator receptor-gamma co-activator 1-alpha (PGC1 alpha), sirtuin 3 (SIRT3) and mitochondrial transcription factor A (TFAM) protein expression in resistant cells. Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1 alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit alpha 2 (AMPK alpha 2) transcripts and protein expression in resistant H1299 cells. mRNA expression was also reduced for cisplatin resistant H1299 cells in these genes, however the pattern was not consistent in resistant P31 cells. There was very little change in DNA methylation of these genes, suggesting that the cells are not stably reprogrammed epigenetically. Taken together, our data demonstrate reduced oxidative metabolism, reduced mitochondrial abundance, potential for increased glycolytic flux and increased ROS production in acquired cisplatin resistant cells. This suggests that the metabolic changes are a result of reduced SIRT3 expression and increased HIF-1 alpha stabilization.

  • 43.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Mechanisms of alloxan diabetogenicity1981Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Suspensions of pancreatic islet cells from ob/ob-mice were incubated with Trypan Blue. Microscope photometry showed that apparently viable cells excluded the dye completely, whereas the nuclei of non-viable cells accumulated Trypan Blue by a saturable process. Alloxan rapidly increased the permeability of the plasma membrane in mouse 3-cells; the exclusion of Trypan Blue is a valid and useful measure of islet cell viability following alloxan exposure.

    The diabetogenic action of alloxan may be mediated by hydroxyl radicals. In several biological systems hydroxyl radicals are formed by an iron-catalyzed reaction between superoxide anion radicals and hydrogen peroxide. To test whether this applies to alloxan diabetogenicity, the effects of superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators were tested (a) in a cell-free radical-generating system and (b) on islets and islet-cells exposed to alloxan In vitro. The effect of longtime-circulating superoxide dismutase injected prior to alloxan was tested on mice in vivo.

    Luminol chemiluminescence was used to monitor alloxan-dependent radical production. Accumulation of 8^Rb+ and exclusion of Trypan Blue were used as cell viability criteria in isolated mouse islets and islet-cells. Blood glucose was determined to monitor the development of diabetes in living animals.

    Superoxide dismutase, catalase, scavengers of hydroxyl radicals, and metal ion chelators inhibited the alloxan-dependent chemiluminescence and decreased the toxic effects on Rb+ accumulation or Trypan Blue exclusion in islets and islet-cells. Superoxide dismutase, linked to polyethylene glycol and injected 12 hours before alloxan, largely prevented the development of alloxan diabetes.

    Alloxan toxicity _in vitro and in vivo seems to depend on the formation of superoxide radicals and hydrogen peroxide which in turn form the noxious hydroxyl radical via an iron-catalyzed Haber-Weiss reaction.

    As free radicals and hydrogen peroxide can be formed by other chemicals and during inflammation, and inflammation may accompany the outbreak of human diabetes, studies on the beneficiary effects of superoxide dismutase and other scavengers of free radicals in other forms of diabetes seem warranted.

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  • 44.
    Grankvist, Kjell
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Gomez, Ruben
    Nybo, Mads
    Lima-Oliveira, Gabriel
    von Meyer, Alexander
    Preanalytical aspects on short- and long-term storage of serum and plasma2019In: Diagnosis, ISSN 2194-8011, E-ISSN 2194-802X, Vol. 6, no 1, p. 51-56Article, review/survey (Refereed)
    Abstract [en]

    Following an ordered clinical chemistry plasma/serum test, ideally the venous blood specimen is adequately collected at a health care facility, then swiftly transported to and readily handled, analyzed and sometimes interpreted at a clinical chemistry laboratory followed by a report of the test result to the ordering physician to finally handle the result. However, often there are practical as well as sample quality reasons for short-or long-term storage of samples before and after analysis. If there are specific storage needs, the preanalytical handling practices are specified in the laboratory's specimen collection instructions for the ordered test analyte. Biobanking of specimens over a very long time prior to analysis includes an often neglected preanalytical challenge for preserved quality of the blood specimen and also involves administrative and additional practical handling aspects (specified in a standard operating procedure SOP) when demands and considerations from academic, industry, research organizations and authorities are included. This short review highlights some preanalytical aspects of plasma/serum short-and long-term storage that must be considered by clinicians, laboratory staff as well as the researchers.

  • 45.
    Grankvist, Kjell
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hammarsten, Ola
    Institutionen för Biomedicin, Göteborgs universitet.
    Berggren Söderlund, Maria
    Klinisk kemi och transfusionsmedicin, Kronoberg.
    Theodorsson, Elvar
    Institutionen för klinisk och experimentell medicin, Linköpings universitet.
    Laboratoriernas verksamhet2018In: Laurells Klinisk kemi i praktisk medicin / [ed] Elvar Theodorsson & Maria Berggren Söderlund, Lund: Studentlitteratur AB, 2018, 10, p. 13-30Chapter in book (Refereed)
  • 46.
    Grankvist, Kjell
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sigthorsson, Gudmundur
    Kristensen, Gunn B.
    Pelanti, Jonna
    Nybo, Mads
    Status on fasting definition for blood sampling in the Nordic countries - time for a harmonized definition2018In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 78, no 7-8, p. 591-594Article in journal (Refereed)
    Abstract [en]

    The preanalytical phase contains a vast number of practices whose variation may influence the results of laboratory testing and should, therefore, be standardized. The Working Group on Preanalytical Phase of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM WG-PA) has suggested a standardization of venous blood specimen collection (VBSC) requirements for fasting samples including 12 h fasting time and water ad lib in the morning prior to specimen collection. The Nordic Scientific Preanalytical Working Group investigated the fasting definitions used in the Nordic countries. The Internet was assessed for stated fasting definitions of official organizations, larger laboratories, or laboratory groups. Fasting instructions for VBSC generally demanded patients to abstain from alcohol a day prior to, and to abstain from coffee, tea, smoking, and snuff intake in the morning of VBSC. Norway had a national fasting definition. Required fasting times varied from 8 to 14 h. The amount of water allowed in the morning of VBSC varied from ad lib to half a glass of water. The list of analytes, where fasting was required, held 9-15 analytes except for Finland with 65 analytes. Implementation of the EFLM WG-PRE standardization of VBSC requirements for fasting samples would decrease preanalytical variability and be beneficial for medical decisions and patient data comparison. We suggest the laboratories in the Nordic countries to implement the suggested fasting requirements, which are in line with those used when fasting reference intervals were established in the Nordic reference interval project.

  • 47. 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.

  • 48.
    Hammarsten, Ola
    et al.
    Institutionen för Biomedicin, Göteborgs universitet.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Theodorsson, Elvar
    Institutionen för klinisk och experimentell medicin, Linköpings universitet.
    Tolkning av analysresultat2018In: Laurells Klinisk kemi i praktisk medicin / [ed] Elvar Theodorsson & Maria Berggren Söderlund, Lund: Studentlitteratur AB, 2018, 10, p. 31-53Chapter in book (Refereed)
  • 49. Holl, Katsiaryna
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kaasila, Marjo
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Afanasyeva, Yelena
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lehtinen, Matti
    Pukkala, Eero
    Surcel, Helja-Marja
    Toniolo, Paolo
    Zeleniuch-Jacquotte, Anne
    Koskela, Pentti
    Lukanova, Annekatrin
    Effect of long-term storage on hormone measurements in samples from pregnant women: the experience of the Finnish Maternity Cohort2008In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, no 3, p. 406-412Article in journal (Refereed)
    Abstract [en]

    Validity of biobank studies on hormone associated cancers depend on the extent the sample preservation is affecting the hormone measurements. We investigated the effect of long-term storage (up to 22 years) on immunoassay measurements of three groups of hormones and associated proteins: sex-steroids [estradiol, progesterone, testosterone, dihydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG)], pregnancy-specific hormones [human chorionic gonadotropin (hCG), placental growth hormone (pGH), alpha-fetoprotein (AFP)], and insulin-like growth factor (IGF) family hormones exploiting the world largest serum bank, the Finnish Maternity Cohort (FMC). Hormones of interest were analyzed in a random sample of 154 Finnish women in the median age (29.5 years, range 25 to 34 years) of their first pregnancy with serum samples drawn during the first trimester. All hormone measurements were performed using commercial enzyme-linked- or radio-immunoassays. Storage time did not correlate with serum levels of testosterone, DHEAS, hCG, pGH and total IGFBP-1. It had a weak or moderate negative correlation with serum levels of progesterone (Spearman's ranked correlation coefficient (rs)=− 0.36), IGF-I (rs=−0.23) and IGF binding protein (BP)-3 (rs=−0.38), and weak positive correlation with estradiol (rs=0.23), SHBG (rs=0.16), AFP (rs=0.20) and non-phosphorylated IGF binding protein (BP)-1 (rs=0.27). The variation of all hormone levels studied followed the kinetics reported for early pregnancy. Bench-lag time (the time between sample collection and freezing for storage) did not materially affect the serum hormone levels. In conclusion, the stored FMC serum samples can be used to study hormone-disease associations, but close matching for storage time and gestational day are necessary design components of all related biobank studies.

  • 50. Holl, Katsiaryna
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Surcel, Heljä-Marja
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Koskela, Pentti
    Dillner, Joakim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olafsdottir, Gudridur H
    Ogmundsdottir, Helga M
    Pukkala, Eero
    Lehtinen, Matti
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lukanova, Annekatrin
    Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: A nested case-referent study.2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 12, p. 2923-2928Article in journal (Refereed)
    Abstract [en]

    According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring. (c) 2009 UICC.

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