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 Roberts, Alison Klein, Sean M. Grimmond, Andrew Biankin, Sean Cleary, Malcolm Moore, Mathieu Lemire, George Zogopoulos, Lincoln Stein, Steven Gallinger

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)719-722.e3
JournalGastroenterology
Volume154
Issue number3
DOIs
StatePublished - Feb 1 2018

Fingerprint

Exome
Pancreatic Neoplasms
Genes
Genetic Heterogeneity
Neoplasm Genes
DNA Repair
Odds Ratio
Genome

Keywords

  • Familial Cancer
  • Inherited Cancer
  • Pancreas
  • Rare Variant Burden Tests

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Grant, R. C., Denroche, R. E., Borgida, A., Virtanen, C., Cook, N., Smith, A. 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

Exome-Wide Association Study of Pancreatic Cancer Risk. / Grant, Robert C.; Denroche, Robert E.; Borgida, Ayelet; Virtanen, Carl; Cook, Natalie; Smith, Alyssa L.; Connor, Ashton A.; Wilson, Julie M.; Peterson, Gloria; Roberts, Nicholas; Klein, Alison; Grimmond, Sean M.; Biankin, Andrew; Cleary, Sean; Moore, Malcolm; Lemire, Mathieu; Zogopoulos, George; Stein, Lincoln; Gallinger, Steven.

In: Gastroenterology, Vol. 154, No. 3, 01.02.2018, p. 719-722.e3.

Research output: Contribution to journalArticle

Grant, RC, Denroche, RE, Borgida, A, Virtanen, C, Cook, N, Smith, AL, Connor, AA, Wilson, JM, Peterson, G, Roberts, N, Klein, A, 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
Grant RC, Denroche RE, Borgida A, Virtanen C, Cook N, Smith AL et al. Exome-Wide Association Study of Pancreatic Cancer Risk. Gastroenterology. 2018 Feb 1;154(3):719-722.e3. https://doi.org/10.1053/j.gastro.2017.10.015
Grant, Robert C. ; Denroche, Robert E. ; Borgida, Ayelet ; Virtanen, Carl ; Cook, Natalie ; Smith, Alyssa L. ; Connor, Ashton A. ; Wilson, Julie M. ; Peterson, Gloria ; Roberts, Nicholas ; Klein, Alison ; Grimmond, Sean M. ; Biankin, Andrew ; Cleary, Sean ; Moore, Malcolm ; Lemire, Mathieu ; Zogopoulos, George ; Stein, Lincoln ; Gallinger, Steven. / Exome-Wide Association Study of Pancreatic Cancer Risk. In: Gastroenterology. 2018 ; Vol. 154, No. 3. pp. 719-722.e3.
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