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

Yao Yu, Kyle Chang, Jiun Sheng Chen, Ryan James Bohlender, Jerry Fowler, Di Zhang, Maosheng Huang, Ping Chang, Yanan Li, Justin Wong, Huamin Wang, Jian Gu, Xifeng Wu, Joellen Schildkraut, Lisa Cannon-Albright, Yuanqing Ye, Hua Zhao, Michelle A.T. Hildebrandt, Jennifer B. Permuth, Donghui LiPaul Scheet, Chad D. Huff

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number100078
JournalHuman Genetics and Genomics Advances
Issue number1
StatePublished - Jan 13 2022


  • Association Analysis
  • ATM
  • Case-Control Study
  • Pancreatic Cancer
  • SIK3

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics(clinical)


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