TY - JOUR
T1 - A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk
AU - Yu, Yao
AU - Chang, Kyle
AU - Chen, Jiun Sheng
AU - Bohlender, Ryan James
AU - Fowler, Jerry
AU - Zhang, Di
AU - Huang, Maosheng
AU - Chang, Ping
AU - Li, Yanan
AU - Wong, Justin
AU - Wang, Huamin
AU - Gu, Jian
AU - Wu, Xifeng
AU - Schildkraut, Joellen
AU - Cannon-Albright, Lisa
AU - Ye, Yuanqing
AU - Zhao, Hua
AU - Hildebrandt, Michelle A.T.
AU - Permuth, Jennifer B.
AU - Li, Donghui
AU - Scheet, Paul
AU - Huff, Chad D.
N1 - Publisher Copyright:
© 2021
PY - 2022/1/13
Y1 - 2022/1/13
N2 - 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.
AB - 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.
KW - ATM
KW - Association Analysis
KW - Case-Control Study
KW - Pancreatic Cancer
KW - SIK3
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U2 - 10.1016/j.xhgg.2021.100078
DO - 10.1016/j.xhgg.2021.100078
M3 - Article
C2 - 35047863
AN - SCOPUS:85121874808
SN - 2666-2477
VL - 3
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 1
M1 - 100078
ER -