Letter | Published:

Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer

Nature Genetics volume 47, pages 911916 (2015) | Download Citation

Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the developed world1. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM3, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A7 and mismatch-repair genes8 and low-penetrance loci are associated with increased risk9,10,11,12. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19–1.34, P = 1.42 × 10−14), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84–0.92, P = 1.41 × 10−8) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85–0.93, P = 2.35 × 10−8). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09–1.19, P = 3.36 × 10−9), a region with previous suggestive evidence in Han Chinese12. We replicated previously reported associations at 9q34.2 (ABO)9, 13q22.1 (KLF5)10, 5p15.33 (TERT and CLPTM1)10,11, 13q12.2 (PDX1)11, 1q32.1 (NR5A2)10, 7q32.3 (LINC-PINT)11, 16q23.1 (BCAR1)11 and 22q12.1 (ZNRF3)11. Our study identifies new loci associated with pancreatic cancer risk.

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Acknowledgements

This work was supported by National Cancer Institute/US National Institutes of Health grant RO1 CA154823. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the US National Institutes of Health to the Johns Hopkins University, contract HHSN268201100011I.

The IARC/Central Europe study was supported by a grant from the National Cancer Institute, US National Institutes of Health (R03 CA123546-02) and by grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3 and MH CZ-DRO-MMCI 00209805).

The work at Johns Hopkins University was supported by National Cancer Institute grants P50 CA62924 and R01 CA97075. Additional support was provided by Susan Wojcicki and Dennis Troper.

The Mayo Clinic Molecular Epidemiology of Pancreatic Cancer study is supported by the Mayo Clinic Specialized Programs of Research Excellence (SPORE) in Pancreatic Cancer (P50 CA102701).

The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry is supported by National Cancer Institute/US National Institutes of Health grant P30 CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Foundation and the Society of the Memorial Sloan Kettering Cancer Center.

The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; grant 442302). R.E.N. is supported by an NHMRC Senior Research Fellowship (1060183).

The University of California San Francisco (UCSF) pancreas study was supported by US National Institutes of Health/National Cancer Institute grants (R01 CA1009767 and R01 CA109767-S1) and the Joan Rombauer Pancreatic Cancer Fund. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program; the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California (CPIC); and the US Centers for Disease Control and Prevention (CDC) National Program of Cancer Registries, under agreement U58 DP003862-01 awarded to the California Department of Public Health.

The Yale (Connecticut) pancreas study is supported by US National Institutes of Health/National Cancer Institute grant 5R01 CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the Department of Public Health Human Investigation Committee of the state of Connecticut. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data.

Studies included in PANDoRA were partly funded by the Czech Science Foundation (P301/12/1734) and the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Ministry of Research, Science and Arts of Baden-Württemberg state (H.B.), the Heidelberger EPZ Pancobank (M.W. Büchler and team; T. Hackert, N.A. Giese, Ch. Tjaden, E. Soyka and M. Meinhardt; Heidelberger Stiftung Chirurgie and BMBF, grant 01GS08114), the BMBH (P. Schirmacher; BMBF grant 01EY1101), Dutch Cancer Society project grant 2012-5607 and the Academic Medical Center Foundation (M.F.B.), the “5x1000” voluntary contribution of the Italian government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54 and RC1303GA50), the Italian Association for Research on Cancer (A. Scarpa; AIRC 12182), the Italian Ministry of Research (A. Scarpa; FIRB-RBAP10AHJB), the Italian FIMP–Ministry of Health (A. Scarpa; CUP_J33G13000210001) and the National Institute for Health Research (NIHR) Liverpool Pancreas Biomedical Research Unit, UK. We would like to acknowledge the contribution of F. Dijk and O. Busch (Academic Medical Center, Amsterdam).

Assistance with genotype data quality control was provided by Cecilia Laurie and Cathy Laurie at the University of Washington Genetic Analysis Center.

Author information

Author notes

    • Erica J Childs
    • , Evelina Mocci
    •  & Daniele Campa

    These authors contributed equally to this work.

Affiliations

  1. Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA.

    • Erica J Childs
  2. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

    • Evelina Mocci
    • , Amanda Blackford
    •  & Alison P Klein
  3. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Daniele Campa
  4. Department of Biology, University of Pisa, Pisa, Italy.

    • Daniele Campa
  5. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.

    • Paige M Bracci
    •  & Elizabeth A Holly
  6. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Steven Gallinger
    •  & Rayjean J Hung
  7. Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

    • Michael Goggins
    • , Michael Borges
    •  & Alison P Klein
  8. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Donghui Li
    •  & Manal Hassan
  9. Department of Population Health, QIMR Berghofer Medical Research Institute, Kelvin Grove,Queensland, Australia.

    • Rachel E Neale
  10. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Sara H Olson
    • , Irene Orlow
    •  & Amethyst Saldia
  11. International Agency for Research on Cancer (IARC), Lyon, France.

    • Ghislaine Scelo
    •  & Paul Brennan
  12. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA.

    • Laufey T Amundadottir
    • , Stephen J Chanock
    •  & Robert N Hoover
  13. Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    • William R Bamlet
    • , Kari G Chaffee
    • , Ann L Oberg
    •  & Gloria M Petersen
  14. Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

    • Maarten F Bijlsma
  15. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

    • Hermann Brenner
  16. Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

    • H Bas Bueno-de-Mesquita
  17. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands.

    • H Bas Bueno-de-Mesquita
  18. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • H Bas Bueno-de-Mesquita
  19. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

    • H Bas Bueno-de-Mesquita
  20. Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Federico Canzian
    •  & Cosmeri Rizzato
  21. Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy.

    • Gabriele Capurso
  22. Università Vita Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy.

    • Giulia M Cavestro
  23. Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada.

    • Sean P Cleary
  24. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

    • Sean P Cleary
  25. Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada.

    • Michelle Cotterchio
  26. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

    • Michelle Cotterchio
  27. Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Medical Faculty Masaryk University, Brno, Czech Republic.

    • Lenka Foretova
  28. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Charles Fuchs
    •  & Brian M Wolpin
  29. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Charles Fuchs
  30. Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy.

    • Niccola Funel
  31. Department of Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.

    • Maria Gazouli
  32. Department of Radiation Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Joseph M Herman
  33. Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.

    • Ivana Holcatova
  34. Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic.

    • Vladimir Janout
  35. Cancer Epidemiology Unit, University of Oxford, Oxford, UK.

    • Timothy J Key
  36. Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.

    • Juozas Kupcinskas
  37. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Robert C Kurtz
  38. Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy.

    • Stefano Landi
  39. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.

    • Lingeng Lu
    •  & Harvey A Risch
  40. Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland.

    • Ewa Malecka-Panas
  41. Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy.

    • Andrea Mambrini
  42. Laboratory of Toxicogenomics, Institute of Public Health, Prague, Czech Republic.

    • Beatrice Mohelnikova-Duchonova
  43. National Institute for Health Research (NIHR) Pancreas Biomedical Research Unit, Liverpool Clinical Trials Unit and Cancer Research UK Clinical Trials Unit, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

    • John P Neoptolemos
  44. Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy.

    • Claudio Pasquali
  45. Pancreas Unit, Department of Digestive Diseases, Sant'Orsola-Malpighi Hospital, Bologna, Italy.

    • Raffaele Pezzilli
  46. ARC-NET–Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.

    • Aldo Scarpa
  47. Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA.

    • Rachael Z Stolzenberg-Solomon
  48. Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.

    • Oliver Strobel
  49. Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.

    • Francesca Tavano
  50. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Yogesh K Vashist
  51. Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic.

    • Pavel Vodicka
  52. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Brian M Wolpin
  53. Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

    • Herbert Yu

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Contributions

D.C., G.M.P., H.A.R. and A.P.K. organized and designed the study. F.C. and A.P.K. organized and supervised the genotyping of samples. E.J.C., E.M., D.C. and A.P.K. designed and conducted the statistical analysis. E.J.C., E.M., M. Goggins and A.P.K. drafted the first version of the manuscript. P.M.B., S.G., M. Goggins, D.L., R.E.N., S.H.O., G.S., L.T.A., W.R.B., M.F.B., A.B., M.B., P.B., H.B., H.B.B.-d.-M., F.C., G.C., G.M.C., K.G.C., S.J.C., S.P.C., M.C., L.F., C.F., N.F., M. Gazouli, M.H., J.M.H., I.H., E.A.H., R.N.H., R.J.H., V.J., T.J.K., J.K., R.C.K., S.L., L.L., E.M.-P., A.M., B.M.-D., J.P.N., A.L.O., I.O., C.P., R.P., C.R., A. Saldia, A. Scarpa, R.Z.S.-S., O.S., F.T., Y.K.V., P.V., B.M.W., H.Y., G.M.P., H.A.R. and A.P.K. contributed samples for the GWAS and/or the replication analysis. All authors contributed to the final version of the manuscript.

Competing interests

Under a licensing agreement between Myriad Genetics, Inc., and the Johns Hopkins University, M. Goggins and A.P.K. are entitled to a share of royalties received by the university on sales of products related to PALB2. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Corresponding author

Correspondence to Alison P Klein.

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DOI

https://doi.org/10.1038/ng.3341

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