A Whole-Exome Case-Control Association Study To Characterize the Contribution of Rare Coding Variation to Pancreatic Cancer Risk

Authors

Yao Yu
Kyle Chang
Jiun-Sheng Chen
Ryan J 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 Li
Paul Scheet
Chad D Huff

Publication Date

1-13-2022

Journal

Human Genetics and Genomics Advances

DOI

10.1016/j.xhgg.2021.100078

PMID

35047863

PMCID

PMC8756505

PubMedCentral® Posted Date

12-10-2021

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Published Open-Access

yes

Recommended Citation

Yu, Yao; Chang, Kyle; Chen, Jiun-Sheng; et al., "A Whole-Exome Case-Control Association Study To Characterize the Contribution of Rare Coding Variation to Pancreatic Cancer Risk" (2022). Faculty, Staff and Student Publications. 2741.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2741