A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic...

Pancreatic cancer is a deadly disease that accounts for approximately 5% of cancer deaths worldwide, with a dismal 5-year survival rate of 10%. Known genetic risk factors explain only a modest proportion of the heritable risk of pancreatic cancer. We conducted a whole-exome case-control sequencing study in 1,591 pancreatic cancer cases and 2,134 cancer-free controls of European ancestry. In our gene-based analysis, ATM ranked first, with a genome-wide significant p value of 1 × 10^-8. The odds ratio for protein-truncating variants in ATM was 24, which is substantially higher than prior estimates, although ours includes a broad 95% confidence interval (4.0-1000). SIK3 was the second highest ranking gene (p = 3.84 × 10^-6, false discovery rate or FDR = 0.032). We observed nominally significant association signals in several genes of a priori interest, including BRCA2 (p = 4.3 × 10^-4), STK11 (p = 0.003), PALB2 (p = 0.019), and TP53 (p = 0.037), and reported risk estimates for known pathogenic variants and variants of uncertain significance (VUS) in these genes. The rare variants in established susceptibility genes explain approximately 24% of log familial relative risk, which is comparable to the contribution from established common susceptibility variants (17%). In conclusion, this study provides new insights into the genetic susceptibility of pancreatic cancer, refining rare variant risk estimates in known pancreatic cancer susceptibility genes and identifying SIK3 as a novel candidate susceptibility gene. This study highlights the prominent importance of ATM truncating variants and the underappreciated role of VUS in pancreatic cancer etiology.