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

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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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.

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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.

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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.

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Correspondence to Alison P Klein.

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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.

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

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