Exome-Wide Association Study of Pancreatic Cancer Risk

Robert C. Grant; Robert E. Denroche; Ayelet Borgida; Carl Virtanen; Natalie Cook; Alyssa L. Smith; Ashton A. Connor; Julie M. Wilson; Gloria Peterson; Nicholas J. Roberts; Alison P. Klein; Sean M. Grimmond; Andrew Biankin; Sean Cleary; Malcolm Moore; Mathieu Lemire; George Zogopoulos; Lincoln Stein; Steven Gallinger

doi:10.1053/j.gastro.2017.10.015

Exome-Wide Association Study of Pancreatic Cancer Risk

Robert C. Grant, Robert E. Denroche, Ayelet Borgida, Carl Virtanen, Natalie Cook, Alyssa L. Smith, Ashton A. Connor, Julie M. Wilson, Gloria Peterson, Nicholas J. Roberts, Alison P. Klein, Sean M. Grimmond, Andrew Biankin, Sean Cleary, Malcolm Moore, Mathieu Lemire, George Zogopoulos, Lincoln Stein, Steven Gallinger

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	719-722.e3
Journal	Gastroenterology
Volume	154
Issue number	3
DOIs	https://doi.org/10.1053/j.gastro.2017.10.015
State	Published - Feb 2018

Keywords

Familial Cancer
Inherited Cancer
Pancreas
Rare Variant Burden Tests

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2017.10.015

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Grant, R. C., Denroche, R. E., Borgida, A., Virtanen, C., Cook, N., Smith, A. L., Connor, A. A., Wilson, J. M., Peterson, G., Roberts, N. J., Klein, A. P., Grimmond, S. M., Biankin, A., Cleary, S., Moore, M., Lemire, M., Zogopoulos, G., Stein, L., & Gallinger, S. (2018). Exome-Wide Association Study of Pancreatic Cancer Risk. Gastroenterology, 154(3), 719-722.e3. https://doi.org/10.1053/j.gastro.2017.10.015

Grant, RC, Denroche, RE, Borgida, A, Virtanen, C, Cook, N, Smith, AL, Connor, AA, Wilson, JM, Peterson, G, Roberts, NJ, Klein, AP, Grimmond, SM, Biankin, A, Cleary, S, Moore, M, Lemire, M, Zogopoulos, G, Stein, L & Gallinger, S 2018, 'Exome-Wide Association Study of Pancreatic Cancer Risk', Gastroenterology, vol. 154, no. 3, pp. 719-722.e3. https://doi.org/10.1053/j.gastro.2017.10.015

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title = "Exome-Wide Association Study of Pancreatic Cancer Risk",

abstract = "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.",

keywords = "Familial Cancer, Inherited Cancer, Pancreas, Rare Variant Burden Tests",

author = "Grant, {Robert C.} and Denroche, {Robert E.} and Ayelet Borgida and Carl Virtanen and Natalie Cook and Smith, {Alyssa L.} and Connor, {Ashton A.} and Wilson, {Julie M.} and Gloria Peterson and Roberts, {Nicholas J.} and Klein, {Alison P.} and Grimmond, {Sean M.} and Andrew Biankin and Sean Cleary and Malcolm Moore and Mathieu Lemire and George Zogopoulos and Lincoln Stein and Steven Gallinger",

note = "Funding Information: The Alzheimer{\textquoteright}s Disease Sequencing Project (ADSP) is comprised of 2 Alzheimer{\textquoteright}s Disease (AD) genetics consortia and 3 National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer{\textquoteright}s Disease Genetics Consortium (ADGC) funded by National Institute on Aging (NIA) (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institutes of Health institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr Seshadri; U01AG049506 to Dr Boerwinkle; U01AG049507 to Dr Wijsman; and U01AG049508 to Dr Goat. Publisher Copyright: {\textcopyright} 2018 AGA Institute",

year = "2018",

month = feb,

doi = "10.1053/j.gastro.2017.10.015",

language = "English (US)",

volume = "154",

pages = "719--722.e3",

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T1 - Exome-Wide Association Study of Pancreatic Cancer Risk

AU - Grant, Robert C.

AU - Denroche, Robert E.

AU - Borgida, Ayelet

AU - Virtanen, Carl

AU - Cook, Natalie

AU - Smith, Alyssa L.

AU - Connor, Ashton A.

AU - Wilson, Julie M.

AU - Peterson, Gloria

AU - Roberts, Nicholas J.

AU - Klein, Alison P.

AU - Grimmond, Sean M.

AU - Biankin, Andrew

AU - Cleary, Sean

AU - Moore, Malcolm

AU - Lemire, Mathieu

AU - Zogopoulos, George

AU - Stein, Lincoln

AU - Gallinger, Steven

N1 - Funding Information: The Alzheimer’s Disease Sequencing Project (ADSP) is comprised of 2 Alzheimer’s Disease (AD) genetics consortia and 3 National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by National Institute on Aging (NIA) (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institutes of Health institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr Seshadri; U01AG049506 to Dr Boerwinkle; U01AG049507 to Dr Wijsman; and U01AG049508 to Dr Goat. Publisher Copyright: © 2018 AGA Institute

PY - 2018/2

Y1 - 2018/2

N2 - 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.

AB - 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.

KW - Familial Cancer

KW - Inherited Cancer

KW - Pancreas

KW - Rare Variant Burden Tests

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JO - Gastroenterology

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ER -

Exome-Wide Association Study of Pancreatic Cancer Risk

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