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Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4

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Abstract

Purpose

The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.

Methods

Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case–control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition.

Results

When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04–1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02–1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12–3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers.

Conclusions

This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case–control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.

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Acknowledgments

This research was supported by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. This study has been funded by the World Cancer Research Fund (Grant No. 2008/51 to PV). For full acknowledgments, please see electronic supplementary material.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK

    Max Leenders, Paolo Vineis & Elio Riboli

  2. Department of Gastroenterology and Hepatology, University Medical Center Utrecht, F02.618, Postal Box 85500, 3508GA, Utrecht, The Netherlands

    Max Leenders & H. Bas Bueno-de-Mesquita

  3. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Samsiddhi Bhattacharjee, Laufey Amundadottir, Geoffrey S. Tobias, Patricia Hartge, Robert N. Hoover, Kai Yu, Demetrius Albanes, Stephen J. Chanock, Amy Hutchinson, Kevin B. Jacobs, Julie B. Mendelsohn & Rachael Z. Stolzenberg-Solomon

  4. HuGeF Foundation, Turin, Italy

    Paolo Vineis

  5. Department of Epidemiology, American Cancer Society, Atlanta, GA, USA

    Victoria Stevens, Andrea LaCroix & Alpa V. Patel

  6. National Institute for Public Health and the Environment, Bilthoven, The Netherlands

    H. Bas Bueno-de-Mesquita

  7. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA

    Xiao-Ou Shu & Wei Zheng

  8. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Laufey Amundadottir & Stephen J. Chanock

  9. Department of Laboratory Medicine/Pathology, School of Medicine, University of Minnesota, Minneapolis, MN, USA

    Myron Gross

  10. Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, NY, USA

    Jean Wactawski-Wende

  11. Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA

    Alan A. Arslan

  12. Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA

    Alan A. Arslan & Anne Zeleniuch-Jacquotte

  13. New York University Cancer Institute, New York, NY, USA

    Alan A. Arslan & Anne Zeleniuch-Jacquotte

  14. Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain

    Eric J. Duell

  15. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Charles S. Fuchs & Brian M. Wolpin

  16. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Charles S. Fuchs, Brian M. Wolpin, Edward L. Giovanucci, Susan E. Hankinson & David J. Hunter

  17. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada

    Steven Gallinger

  18. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

    Elizabeth A. Holly & Paige M. Bracci

  19. Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA

    Eric J. Jacobs

  20. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Alison P. Klein

  21. Department of Epidemiology, Johns Hopkins Medical Institutions, The Bloomberg School of Public Heath, The Sol Goldman Pancreatic Research Center, Baltimore, MD, USA

    Alison P. Klein

  22. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Charles Kooperberg & Margaret T. Mandelson

  23. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Donghui Li

  24. Group Health Center for Health Studies, Seattle, WA, USA

    Margaret T. Mandelson

  25. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Sara H. Olson

  26. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Gloria Petersen & Kari G. Rabe

  27. Yale University School of Public Health, New Haven, CT, USA

    Harvey A. Risch & Herbert Yu

  28. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

    Ilir Agalliu

  29. INSERM, Institut Gustave-Roussy, Paris-Sud University, Villejuif, France

    Marie-Christine Boutron-Ruault

  30. Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Julie E. Buring

  31. Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA, USA

    Julie E. Buring

  32. Division of Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany

    Federico Canzian

  33. Comprehensive Digestive Disease Center, University of California, Irvine Medical Center, Orange, CA, USA

    Kenneth Chang

  34. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    Michelle Cotterchio

  35. Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada

    Michelle Cotterchio

  36. Physicians’ Health Study, Divisions of Aging, Cardiovascular Medicine, and Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    J. Michael Gaziano

  37. Veterans Affairs Boston Healthcare System, Massachusetts Veterans Epidemiology Research and Information Center, Boston, MA, USA

    J. Michael Gaziano

  38. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Edward L. Giovanucci, Susan E. Hankinson, David J. Hunter, Peter Kraft & Dimitrios Trichopoulos

  39. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

    Edward L. Giovanucci

  40. Departments of Oncology, Pathology and Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michael Goggins

  41. Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden

    Göran Hallmans

  42. Department of Epidemiology, The Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Judith A. Hoffman-Bolton & Kala Visvanathan

  43. Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA

    Amy Hutchinson & Kevin B. Jacobs

  44. Bioinformed Consulting Services, Gaithersburg, MD, USA

    Kevin B. Jacobs

  45. International Agency for Research on Cancer (IARC/WHO), Lyon, France

    Mazda Jenab

  46. Department of Public Health and Primary Care, Clinical Gerontology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK

    Kay-Tee Khaw

  47. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    Peter Kraft

  48. Nutritional Epidemiology Unit, Fondazione Istituto di Recovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy

    Vittorio Krogh

  49. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Robert C. Kurtz

  50. Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA

    Robert R. McWilliams

  51. Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark

    Anne Tjønneland

  52. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece

    Dimitrios Trichopoulos

  53. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland

    Jarmo Virtamo

  54. Division of Cancer Prevention and Population Control, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Joanne W. Elena

Authors
  1. Max Leenders
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  2. Samsiddhi Bhattacharjee
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  3. Paolo Vineis
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  4. Victoria Stevens
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Corresponding author

Correspondence to Max Leenders.

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Leenders, M., Bhattacharjee, S., Vineis, P. et al. Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4. Cancer Causes Control 24, 595–602 (2013). https://doi.org/10.1007/s10552-012-0138-0

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