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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2: Manhattan plot of PanC4 association analysis.
Figure 3: Manhattan plot of combined stage 1 association analysis.
Figure 4: Regional association and LD plots for four new genome-wide significant loci.


  1. 1

    Ferlay, J. et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer (2013).

  2. 2

    Goggins, M. et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 56, 5360–5364 (1996).

    CAS  PubMed  Google Scholar 

  3. 3

    Roberts, N.J. et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2, 41–46 (2012).

    CAS  Article  Google Scholar 

  4. 4

    Jones, S. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324, 217 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Thompson, D., Easton, D.F. & Consortium, B.C.L. Cancer incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 94, 1358–1365 (2002).

    CAS  Article  Google Scholar 

  6. 6

    van Lier, M.G. et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am. J. Gastroenterol. 105, 1258–1264, author reply 1265 (2010).

    CAS  Article  Google Scholar 

  7. 7

    Vasen, H.F. 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 87, 809–811 (2000).

    CAS  Article  Google Scholar 

  8. 8

    Lynch, H.T., Voorhees, G.J., Lanspa, S.J., McGreevy, P.S. & Lynch, J.F. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br. J. Cancer 52, 271–273 (1985).

    CAS  Article  Google Scholar 

  9. 9

    Amundadottir, L. et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat. Genet. 41, 986–990 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Petersen, G.M. et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat. Genet. 42, 224–228 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Wolpin, B.M. et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat. Genet. 46, 994–1000 (2014).

    CAS  Article  Google Scholar 

  12. 12

    Wu, C. et al. Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat. Genet. 44, 62–66 (2012).

    CAS  Article  Google Scholar 

  13. 13

    Low, S.K. et al. Genome-wide association study of pancreatic cancer in Japanese population. PLoS ONE 5, e11824 (2010).

    Article  Google Scholar 

  14. 14

    Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G.R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

    CAS  Article  Google Scholar 

  15. 15

    1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  16. 16

    Altshuler, D.M. et al. Integrating common and rare genetic variation in diverse human populations. Nature 467, 52–58 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).

    CAS  Article  Google Scholar 

  18. 18

    Campa, D. et al. Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium. Dig. Liver Dis. 45, 95–99 (2013).

    CAS  Article  Google Scholar 

  19. 19

    Ward, L.D. & Kellis, M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012).

    CAS  Article  Google Scholar 

  20. 20

    Hoskins, J.W. et al. Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A. Carcinogenesis 35, 2670–2678 (2014).

    CAS  Article  Google Scholar 

  21. 21

    Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).

    CAS  Article  Google Scholar 

  22. 22

    Hegele, R.A., Cao, H., Harris, S.B., Hanley, A.J. & Zinman, B. The hepatic nuclear factor-1α G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J. Clin. Endocrinol. Metab. 84, 1077–1082 (1999).

    CAS  PubMed  Google Scholar 

  23. 23

    Everhart, J. & Wright, D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. J. Am. Med. Assoc. 273, 1605–1609 (1995).

    CAS  Article  Google Scholar 

  24. 24

    Li, D. et al. Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-control studies. Cancer Causes Control 22, 189–197 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Chari, S.T. et al. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 129, 504–511 (2005).

    Article  Google Scholar 

  26. 26

    Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Pierce, B.L. & Ahsan, H. Genome-wide “pleiotropy scan” identifies HNF1A region as a novel pancreatic cancer susceptibility locus. Cancer Res. 71, 4352–4358 (2011).

    CAS  Article  Google Scholar 

  28. 28

    Li, D. et al. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis 33, 1384–1390 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Bergholz, J. & Xiao, Z.X. Role of p63 in development, tumorigenesis and cancer progression. Cancer Microenviron. 5, 311–322 (2012).

    CAS  Article  Google Scholar 

  30. 30

    Flores, E.R. et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 7, 363–373 (2005).

    CAS  Article  Google Scholar 

  31. 31

    Melino, G. p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death Differ. 18, 1487–1499 (2011).

    CAS  Article  Google Scholar 

  32. 32

    Danilov, A.V. et al. DeltaNp63alpha-mediated induction of epidermal growth factor receptor promotes pancreatic cancer cell growth and chemoresistance. PLoS ONE 6, e26815 (2011).

    CAS  Article  Google Scholar 

  33. 33

    Figueroa, J.D. et al. Genome-wide association study identifies multiple loci associated with bladder cancer risk. Hum. Mol. Genet. 23, 1387–1398 (2014).

    CAS  Article  Google Scholar 

  34. 34

    Lan, Q. et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat. Genet. 44, 1330–1335 (2012).

    CAS  Article  Google Scholar 

  35. 35

    Shiraishi, K. et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat. Genet. 44, 900–903 (2012).

    CAS  Article  Google Scholar 

  36. 36

    Miki, D. et al. Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat. Genet. 42, 893–896 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Rothman, N. et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat. Genet. 42, 978–984 (2010).

    CAS  Article  Google Scholar 

  38. 38

    Borowski, A. et al. Structure and function of ETAA16: a novel cell surface antigen in Ewing's tumours. Cancer Immunol. Immunother. 55, 363–374 (2006).

    CAS  Article  Google Scholar 

  39. 39

    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. 37, 13–19 (2014).

    CAS  Article  Google Scholar 

  40. 40

    Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).

    CAS  Article  Google Scholar 

  41. 41

    Avis, I. et al. Effect of gastrin-releasing peptide on the pancreatic tumor cell line (Capan). Mol. Carcinog. 8, 214–220 (1993).

    CAS  Article  Google Scholar 

  42. 42

    Jiang, H. et al. Expression of Gli1 and Wnt2B correlates with progression and clinical outcome of pancreatic cancer. Int. J. Clin. Exp. Pathol. 7, 4531–4538 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460 (1996).

    CAS  Article  Google Scholar 

  44. 44

    Fuchs, C.S. et al. A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch. Intern. Med. 156, 2255–2260 (1996).

    CAS  Article  Google Scholar 

  45. 45

    Iodice, S., Gandini, S., Maisonneuve, P. & Lowenfels, A.B. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch. Surg. 393, 535–545 (2008).

    Article  Google Scholar 

  46. 46

    Jang, J.H., Cotterchio, M., Borgida, A., Gallinger, S. & Cleary, S.P. Genetic variants in carcinogen-metabolizing enzymes, cigarette smoking and pancreatic cancer risk. Carcinogenesis 33, 818–827 (2012).

    CAS  Article  Google Scholar 

  47. 47

    Talamini, R. et al. Tobacco smoking, alcohol consumption and pancreatic cancer risk: a case-control study in Italy. Eur. J. Cancer 46, 370–376 (2010).

    CAS  Article  Google Scholar 

  48. 48

    Urayama, K.Y. 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 129, 2875–2884 (2011).

    CAS  Article  Google Scholar 

  49. 49

    Klein, A.P. et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 64, 2634–2638 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Brune, K.A. et al. Importance of age of onset in pancreatic cancer kindreds. J. Natl. Cancer Inst. 102, 119–126 (2010).

    Article  Google Scholar 

  51. 51

    McWilliams, R.R. et al. Polymorphisms in DNA repair genes, smoking, and pancreatic adenocarcinoma risk. Cancer Res. 68, 4928–4935 (2008).

    CAS  Article  Google Scholar 

  52. 52

    Hassan, M.M. et al. Risk factors for pancreatic cancer: case-control study. Am. J. Gastroenterol. 102, 2696–2707 (2007).

    Article  Google Scholar 

  53. 53

    Olson, S.H. et al. Allergies, variants in IL-4 and IL-4Rα genes, and risk of pancreatic cancer. Cancer Detect. Prev. 31, 345–351 (2007).

    CAS  Article  Google Scholar 

  54. 54

    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 121, 2241–2245 (2007).

    CAS  Article  Google Scholar 

  55. 55

    Tran, B. et al. Association between ultraviolet radiation, skin sun sensitivity and risk of pancreatic cancer. Cancer Epidemiol. 37, 886–892 (2013).

    Article  Google Scholar 

  56. 56

    Duell, E.J. et al. Detecting pathway-based gene-gene and gene-environment interactions in pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 17, 1470–1479 (2008).

    CAS  Article  Google Scholar 

  57. 57

    Risch, H.A. Etiology of pancreatic cancer, with a hypothesis concerning the role of N-nitroso compounds and excess gastric acidity. J. Natl. Cancer Inst. 95, 948–960 (2003).

    CAS  Article  Google Scholar 

  58. 58

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    CAS  Article  Google Scholar 

  59. 59

    Zheng, X. et al. A high-performance computing toolset for relatedness and principal component analysis of SNP data. Bioinformatics 28, 3326–3328 (2012).

    CAS  Article  Google Scholar 

  60. 60

    Mailman, M.D. et al. The NCBI dbGaP database of genotypes and phenotypes. Nat. Genet. 39, 1181–1186 (2007).

    CAS  Article  Google Scholar 

  61. 61

    Tryka, K.A. et al. NCBI's Database of Genotypes and Phenotypes: dbGaP. Nucleic Acids Res. 42, D975–D979 (2014).

    CAS  Article  Google Scholar 

  62. 62

    Delaneau, O., Zagury, J.F. & Marchini, J. Improved whole-chromosome phasing for disease and population genetic studies. Nat. Methods 10, 5–6 (2013).

    CAS  Article  Google Scholar 

  63. 63

    Marchini, J. & Howie, B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 11, 499–511 (2010).

    CAS  Article  Google Scholar 

  64. 64

    Lee, S.H., Wray, N.R., Goddard, M.E. & Visscher, P.M. Estimating missing heritability for disease from genome-wide association studies. Am. J. Hum. Genet. 88, 294–305 (2011).

    Article  Google Scholar 

Download references


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




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.

Corresponding author

Correspondence to Alison P Klein.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1–7. (PDF 1941 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Childs, E., Mocci, E., Campa, D. et al. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. Nat Genet 47, 911–916 (2015).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing