Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. 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 Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

] Cancer Care Ontario University of Toronto Toronto Ontario Canada [2] Dalla Lana School of Public Health University of Toronto Toronto Ontario Canada

] Department for Determinants of Chronic Diseases Bilthoven the Netherlands [2] Department of Gastroenterology and Hepatology University Medical Centre Utrecht the Netherlands [3] Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK [4] Department of Social and Preventive Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

] Department of Medical Oncology Dana Farber Cancer Institute Boston Massachusetts USA [2] Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

] Department of Medical Oncology Dana Farber Cancer Institute Boston Massachusetts USA [2] Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts USA

] Department of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore Maryland USA [2] Department of Pathology Sol Goldman Pancreatic Cancer Research Center Johns Hopkins School of Medicine Baltimore Maryland USA

] Department of Surgery University Health Network University of Toronto Toronto Ontario Canada [2] Princess Margaret Cancer Center University Health Network Toronto Ontario Canada

] Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany [2] Department of Biology University of Pisa Pisa Italy

ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy

Cancer Epidemiology Unit University of Oxford Oxford UK

Department of Biology Section of Genetics University of Pisa Pisa Italy

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute and Medical Faculty Masaryk University Brno Czech Republic

Department of Chronic Disease Epidemiology Yale School of Public Health New Haven Connecticut USA

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York USA

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco California USA

Department of Epidemiology Johns Hopkins School of Public Health Baltimore Maryland USA

Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania

Department of Gastrointestinal Medical Oncology University of Texas MD Anderson Cancer Center Houston Texas USA

Department of General Surgery University Hospital Heidelberg Heidelberg Germany

Department of General Visceral and Thoracic Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Health Sciences Research Mayo Clinic College of Medicine Rochester Minnesota USA

Department of Medical Sciences Laboratory of Biology School of Medicine University of Athens Athens Greece

Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Sciences Prague Czech Republic

Department of Oncology Azienda USL 1 Massa Carrara Massa Carrara Italy

Department of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore Maryland USA

Department of Pathology Sol Goldman Pancreatic Cancer Research Center Johns Hopkins School of Medicine Baltimore Maryland USA

Department of Population Health QIMR Berghofer Medical Research Institute Kelvin Grove Queensland Australia

Department of Preventive Medicine Faculty of Medicine Palacky University Olomouc Czech Republic

Department of Radiation Oncology Sol Goldman Pancreatic Cancer Research Center Johns Hopkins University School of Medicine Baltimore Maryland USA

Department of Surgery Gastroenterology and Oncology University of Padua Padua Italy

Department of Surgery Unit of Experimental Surgical Pathology University Hospital of Pisa Pisa Italy

Digestive and Liver Disease Unit 'Sapienza' University of Rome Rome Italy

Division of Cancer Epidemiology and Genetics National Cancer Institute US National Institutes of Health US Department of Health and Human Services Bethesda Maryland USA

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Gastroenterology and Research Laboratory IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza' San Giovanni Rotondo Italy

Epidemiology Program University of Hawaii Cancer Center Honolulu Hawaii USA

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague Prague Czech Republic

International Agency for Research on Cancer Lyon France

Laboratory for Experimental Oncology and Radiobiology Academic Medical Center University of Amsterdam Amsterdam the Netherlands

Laboratory of Toxicogenomics Institute of Public Health Prague Czech Republic

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada

National Institute for Health Research 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

Nutritional Epidemiology Branch Division of Cancer Epidemiology and Genetics National Cancer Institute US National Institutes of Health Rockville Maryland USA

Pancreas Unit Department of Digestive Diseases Sant'Orsola Malpighi Hospital Bologna Italy

Università Vita Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele Milan Italy

See more in PubMed

Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer; 2013. (online). http://globocan.iarc.fr.

Goggins M, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996;56:5360–4. PubMed

Roberts NJ, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6. PubMed PMC

Jones S, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217. PubMed PMC

Thompson D, Easton DF, Consortium BCL. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94:1358–65. PubMed

van Lier MG, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105:1258–64. author reply 1265. PubMed

Vasen HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden) Int J Cancer. 2000;87:809–11. PubMed

Lynch HT, Voorhees GJ, Lanspa SJ, McGreevy PS, Lynch JF. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br J Cancer. 1985;52:271–3. PubMed PMC

Amundadottir L, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41:986–90. PubMed PMC

Petersen GM, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;42:224–8. PubMed PMC

Wolpin BM, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet. 2014;46:994–1000. PubMed PMC

Wu C, et al. Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat Genet. 2012;44:62–6. PubMed

Low SK, et al. Genome-wide association study of pancreatic cancer in Japanese population. PLoS One. 2010;5:e11824. PubMed PMC

Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet. 2012;44:955–9. PubMed PMC

Abecasis GR, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65. PubMed PMC

Altshuler DM, et al. Integrating common and rare genetic variation in diverse human populations. Nature. 2010;467:52–8. PubMed PMC

Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1. PubMed PMC

Campa D, et al. Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium. Dig Liver Dis. 2013;45:95–9. PubMed

Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–4. PubMed PMC

Hoskins JW, et al. Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. Carcinogenesis. 2014 PubMed PMC

Voight BF, et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet. 2010;42:579–89. PubMed PMC

Hegele RA, Cao H, Harris SB, Hanley AJ, Zinman B. The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab. 1999;84:1077–82. PubMed

Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. Jama. 1995;273:1605–9. PubMed

Li D, et al. Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-control studies. Cancer Causes Control. 2011;22:189–97. PubMed PMC

Chari ST, et al. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology. 2005;129:504–11. PubMed PMC

Yamagata K, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996;384:455–8. PubMed

Pierce BL, Ahsan H. Genome-wide “pleiotropy scan” identifies HNF1A region as a novel pancreatic cancer susceptibility locus. Cancer Res. 2011;71:4352–8. PubMed PMC

Li D, et al. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis. 2012;33:1384–90. PubMed PMC

Bergholz J, Xiao ZX. Role of p63 in Development, Tumorigenesis and Cancer Progression. Cancer Microenviron. 2012;5:311–22. PubMed PMC

Flores ER, et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell. 2005;7:363–73. PubMed

Melino G. p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death Differ. 2011;18:1487–99. PubMed PMC

Danilov AV, et al. DeltaNp63alpha-mediated induction of epidermal growth factor receptor promotes pancreatic cancer cell growth and chemoresistance. PLoS One. 2011;6:e26815. PubMed PMC

Figueroa JD, et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum Mol Genet. 2014;23:1387–98. PubMed PMC

Lan Q, et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet. 2012;44:1330–5. PubMed PMC

Shiraishi K, et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat Genet. 2012;44:900–3. PubMed

Miki D, et al. Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat Genet. 2010;42:893–6. PubMed

Rothman N, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42:978–84. PubMed PMC

Borowski A, et al. Structure and function of ETAA16: a novel cell surface antigen in Ewing’s tumours. Cancer Immunol Immunother. 2006;55:363–74. PubMed PMC

Marlaire S, Van Schaftingen E, Veiga-da-Cunha M. C7orf10 encodes succinate-hydroxymethylglutarate CoA-transferase, the enzyme that converts glutarate to glutaryl-CoA. J Inherit Metab Dis. 2014;37:13–9. PubMed

Son J, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496:101–5. PubMed PMC

Avis I, et al. Effect of gastrin-releasing peptide on the pancreatic tumor cell line (Capan) Mol Carcinog. 1993;8:214–20. PubMed

Jiang H, et al. Expression of Gli1 and Wnt2B correlates with progression and clinical outcome of pancreatic cancer. Int J Clin Exp Pathol. 2014;7:4531–8. PubMed PMC

Yamagata K, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996;384:458–60. PubMed

Fuchs CS, et al. A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch Intern Med. 1996;156:2255–60. PubMed

Iodice S, Gandini S, Maisonneuve P, Lowenfels AB. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg. 2008;393:535–45. PubMed

Jang JH, Cotterchio M, Borgida A, Gallinger S, Cleary SP. Genetic variants in carcinogen-metabolizing enzymes, cigarette smoking and pancreatic cancer risk. Carcinogenesis. 2012;33:818–27. PubMed PMC

Talamini R, et al. Tobacco smoking, alcohol consumption and pancreatic cancer risk: a case-control study in Italy. Eur J Cancer. 2010;46:370–6. PubMed

Urayama KY, et al. Body mass index and body size in early adulthood and risk of pancreatic cancer in a central European multicenter case-control study. Int J Cancer. 2011;129:2875–84. PubMed PMC

Klein AP, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Research. 2004;64:2634–2638. PubMed

Brune KA, et al. Importance of Age of Onset in Pancreatic Cancer Kindreds. Journal of the National Cancer Institute. 2010;102:119–126. PubMed PMC

McWilliams RR, et al. Polymorphisms in DNA repair genes, smoking, and pancreatic adenocarcinoma risk. Cancer Res. 2008;68:4928–35. PubMed PMC

Hassan MM, et al. Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol. 2007;102:2696–707. PubMed PMC

Olson SH, et al. Allergies, variants in IL-4 and IL-4R alpha genes, and risk of pancreatic cancer. Cancer Detect Prev. 2007;31:345–51. PubMed

Eppel A, Cotterchio M, Gallinger S. Allergies are associated with reduced pancreas cancer risk: A population-based case-control study in Ontario, Canada. Int J Cancer. 2007;121:2241–5. PubMed

Tran B, et al. Association between ultraviolet radiation, skin sun sensitivity and risk of pancreatic cancer. Cancer Epidemiol. 2013;37:886–92. PubMed

Duell EJ, et al. Detecting pathway-based gene-gene and gene-environment interactions in pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:1470–9. PubMed PMC

Risch HA. Etiology of pancreatic cancer, with a hypothesis concerning the role of N-nitroso compounds and excess gastric acidity. J Natl Cancer Inst. 2003;95:948–60. PubMed

Purcell S, et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics. 2007;81 PubMed PMC

Zheng X, et al. A high-performance computing toolset for relatedness and principal component analysis of SNP data. Bioinformatics. 2012;28:3326–8. PubMed PMC

Mailman MD, et al. The NCBI dbGaP database of genotypes and phenotypes. Nat Genet. 2007;39:1181–6. PubMed PMC

Tryka KA, et al. NCBI’s Database of Genotypes and Phenotypes: dbGaP. Nucleic Acids Res. 2014;42:D975–9. PubMed PMC

Delaneau O, Zagury JF, Marchini J. Improved whole-chromosome phasing for disease and population genetic studies. Nat Methods. 2013;10:5–6. PubMed

Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet. 2010;11:499–511. PubMed

Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75. PubMed PMC

Lee SH, Wray NR, Goddard ME, Visscher PM. Estimating missing heritability for disease from genome-wide association studies. Am J Hum Genet. 2011;88:294–305. PubMed PMC

Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians

Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

Genetic Susceptibility in Understanding of Pancreatic Ductal Adenocarcinoma Risk: A Decade-Long Effort of the PANDORA Consortium

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival

Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer

Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk