Abstract
We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74–0.84, P = 3.0 × 10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30–1.65, P = 1.1 × 10−10), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10–1.20, P = 2.4 × 10−9) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12–1.25, P = 1.2 × 10−8). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76–0.85, P = 9.8 × 10−14). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
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Acknowledgements
This project was funded in whole or in part with federal funds from the National Cancer Institute (NCI), US National Institutes of Health (NIH) under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, and mention of trade names, commercial products or organizations does not imply endorsement by the US government. Major support for PanScan III sample identification and processing was provided by the Lustgarten Foundation for Pancreatic Cancer Research. Additional support was received from NIH/NCI K07 CA140790, the American Society of Clinical Oncology Conquer Cancer Foundation, the Howard Hughes Medical Institute, the Lustgarten Foundation, the Robert T. and Judith B. Hale Fund for Pancreatic Cancer Research and Promises for Purple to B.M.W. A full list of acknowledgments for each participating study is provided in the Supplementary Note.
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B.M.W., C.R., P.K., C.K., G.M.P., P.H., C.F., S.J.C., R.S.S.-S. and L.T.A. organized and designed the study. B.M.W., C.R., F.C., L.B., R.S.S.-S. and L.T.A. conducted and supervised the genotyping of samples. B.M.W., C.R., P.K., C.K., Z.W., R.B., R.S.S.-S. and L.T.A. contributed to the design and execution of statistical analyses. B.M.W., R.S.S.-S. and L.T.A. wrote the first draft of the manuscript. B.M.W., C.R., P.K., C.K., G.M.P., A.A.A., L.B.-F., P.M.B., J.B., F.C., E.J.D., S.G., G.G.G., G.E.G., P.J.G., E.J.J., A.K., A.P.K., L.N.K., M.H.K., D.L., N.M., S.H.O., H.A.R., H.D.S., K.V., E.W., W.Z., C.C.A., D.A., G.A., M.A.A., D.B., S.I.B., M.-C.B.-R., M.B., M.W.B., H.B.B.-d.-M., P.B., D.C., N.E.C., G.C., C.C., M.C., E.C., J.E., N.F., J.M.G., N.A.G., E.L.G., M. Goggins, M.J.G., M. Gross, C.A.H., M.H., K.J.H., B.E.H., E.A.H., N.H., D.J.H., F.I., M.J., R.K., T.J.K., K.-T.K., E.A.K., M.K., V.K., J.K., R.C.K., A.L., M.T.L., S.L., L.L.M., A.M., S.M., R.L.M., Y.N., A.L.O., K.O., A.V.P., P.H.M.P., U.P., R.P., A.P., M.P., F.X.R., E.R., N.R., A.S., X.-O.S., D.T.S., P.S., M.S., R.T.-W., P.R.T., G.E.T., M.T., A.T., G.S.T., D.T., P.V., J.W.-W., N.W., C.W., H.Y., K.Y., A.Z.-J., R.H., P.H., C.F., S.J.C., R.S.S.-S. and L.T.A. conducted the epidemiological studies and contributed samples to the GWAS and/or follow-up genotyping. All authors contributed to the writing of the manuscript.
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Supplementary Figure 1 Flow diagram of PanScan III study design
A schematic figure showing stage 1, stage 2 and replication stage with a total of 7,683 case and 14,397 control subjects included in the final analysis. Numbers of cases and controls in each stage are indicated as well as the array type, imputation and P- value threshold for SNPs moved forward to replication.
Supplementary Figure 2 Risk allele counts (a) and odds ratios (95% confidence intervals) (b) for pancreatic cancer for a genetic risk score of the ten susceptibility loci identified in PanScan I, II, and III.
(a) Percentage of cases and controls with each total number of risk alleles. Absolute number of participants provided above each vertical bar. (b) Results from unconditional logistic regression of the pancreatic cancer genotype score in participants from Stage 1 and Stage 2 of the PanScan III GWAS. For stage 1, model adjusted for age, sex, geographic region, and significant principal components. For stage 2, model adjusted for age, sex, study, and significant principal components. Referent is the most prevalent risk allele count in controls (n=10 risk alleles).
Supplementary Figure 3 Plot of estimated admixture for individuals in stage 1 of PanScan III GWAS.
For details, see Online Methods. Individuals with <80% European ancestry were excluded from the main association analysis. Individuals with Asian ancestry from SMWHS were analyzed separately and included case and control subjects from SMWHS in stages 1 and 2 of PanScan III and control subjects from SMWHS that were previously genotyped.
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Supplementary Figures 1–6, Supplementary Tables 1–12 and Supplementary Note (PDF 2802 kb)
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Wolpin, B., Rizzato, C., Kraft, P. et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet 46, 994–1000 (2014). https://doi.org/10.1038/ng.3052
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DOI: https://doi.org/10.1038/ng.3052
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