Exome-Wide Association Study of Pancreatic Cancer Risk

被引：38

作者：

Grant, Robert C. ^{[1
]}

Denroche, Robert E. ^{[1
]}

Borgida, Ayelet ^{[2
]}

Virtanen, Carl ^{[3
]}

Cook, Natalie ^{[3
]}

Smith, Alyssa L. ^{[4
]}

Connor, Ashton A. ^{[1
]}

Wilson, Julie M. ^{[1
]}

Peterson, Gloria ^{[5
]}

Roberts, Nicholas J. ^{[6
]}

Klein, Alison P. ^{[6
,7
]}

Grimmond, Sean M. ^{[8
]}

Biankin, Andrew ^{[9
,10
,11
]}

Cleary, Sean ^{[1
,2
]}

Moore, Malcolm ^{[3
]}

Lemire, Mathieu ^{[1
]}

Zogopoulos, George ^{[4
]}

Stein, Lincoln ^{[1
]}

Gallinger, Steven ^{[1
,2
]}

机构：

[1] Ontario Inst Canc Res, Toronto, ON, Canada

[2] Ontario Pancreas Canc Study, Toronto, ON, Canada

[3] Princess Margaret Genom Ctr, Toronto, ON, Canada

[4] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada

[5] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[6] Johns Hopkins Med Inst, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA

[7] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Dept Pathol, Baltimore, MD 21205 USA

[8] Univ Melbourne, Ctr Canc Res, Victorian Comprehens Canc Ctr, Melbourne, Vic, Australia

[9] Univ Glasgow, Inst Canc Sci, Wohl Canc Res Ctr, Glasgow, Lanark, Scotland

[10] Glasgow Royal Infirm, West Scotland Pancreat Unit, Glasgow, Lanark, Scotland

[11] Univ NSW, Fac Med, South Western Sydney Clin Sch, Liverpool, NSW, Australia

来源：

GASTROENTEROLOGY | 2018年 / 154卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Pancreas; Familial Cancer; Inherited Cancer; Rare Variant Burden Tests; SUSCEPTIBILITY; MUTATIONS; RARE; FRAMEWORK; VARIANTS; GENES;

D O I：

10.1053/j.gastro.2017.10.015

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10(-6); exome-wide statistical significance threshold P < 2.5x10(-6)). Cases had more rare inactivating variants in DNA repair genes than controls, even after excluding 13 genes known to predispose to pancreatic cancer (adjusted odds ratio, 1.35; P = .045). At the suggestive threshold (P < .001), 6 genes were enriched for rare damaging variants (UHMK1, AP1G2, DNTA, CHST6, FGFR3, and EPHA1) and 7 genes had associations with pancreatic cancer risk, based on the sequence-kernel association test. We confirmed variants in BRCA2 as the most common high-penetrant genetic factor associated with pancreatic cancer and we also identified candidate pancreatic cancer genes. Large collaborations and novel approaches are needed to overcome the genetic heterogeneity of pancreatic cancer predisposition.

引用

页码：719 / +

页数：7

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