The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes

Clinical Cancer Genomics Community Research Network (Ccgcrn)

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Approximately 5–10% of all pancreatic cancer patients carry a predisposing mutation in a known susceptibility gene. Since >90% of patients present with late stage disease, it is crucial to identify high risk individuals who may be amenable to early detection or other prevention. To explore the spectrum of hereditary pancreatic cancer susceptibility, we evaluated germline DNA from pancreatic cancer participants (n = 53) from a large hereditary cancer registry. For those without a known predisposition mutation gene (n = 49), germline next generation sequencing was completed using targeted capture for 706 candidate genes. We identified 16 of 53 participants (30%) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13%) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)]. Many had mutations in Fanconi anemia complex genes [BRCA2 (3 participants), FANCF, FANCM]. Eight participants had rare protein truncating variants of uncertain significance with no other P or LP variants. Earlier age of pancreatic cancer diagnosis (57.5 vs 64.8 years) was indicative of possessing a P or LP variant, as was cancer family history (p values <0.0001). Our multigene panel approach for identifying known cancer predisposing genetic susceptibility in those at risk for hereditary pancreatic cancer may have direct applicability to clinical practice in cases with mutations in actionable genes. Future pancreatic cancer predisposition studies should include evaluation of the Fanconi anemia genes.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalFamilial Cancer
DOIs
StateAccepted/In press - Jul 8 2017

Fingerprint

Fanconi Anemia
Pancreatic Neoplasms
Genes
Mutation
Neoplasms
BRCA2 Gene
Genetic Predisposition to Disease
Registries
DNA

Keywords

  • BRCA2
  • Germline
  • Hereditary
  • Pancreatic cancer
  • Susceptibility

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Genetics(clinical)
  • Cancer Research

Cite this

The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. / Clinical Cancer Genomics Community Research Network (Ccgcrn).

In: Familial Cancer, 08.07.2017, p. 1-11.

Research output: Contribution to journalArticle

Clinical Cancer Genomics Community Research Network (Ccgcrn). / The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. In: Familial Cancer. 2017 ; pp. 1-11.
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abstract = "Approximately 5–10{\%} of all pancreatic cancer patients carry a predisposing mutation in a known susceptibility gene. Since >90{\%} of patients present with late stage disease, it is crucial to identify high risk individuals who may be amenable to early detection or other prevention. To explore the spectrum of hereditary pancreatic cancer susceptibility, we evaluated germline DNA from pancreatic cancer participants (n = 53) from a large hereditary cancer registry. For those without a known predisposition mutation gene (n = 49), germline next generation sequencing was completed using targeted capture for 706 candidate genes. We identified 16 of 53 participants (30{\%}) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13{\%}) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)]. Many had mutations in Fanconi anemia complex genes [BRCA2 (3 participants), FANCF, FANCM]. Eight participants had rare protein truncating variants of uncertain significance with no other P or LP variants. Earlier age of pancreatic cancer diagnosis (57.5 vs 64.8 years) was indicative of possessing a P or LP variant, as was cancer family history (p values <0.0001). Our multigene panel approach for identifying known cancer predisposing genetic susceptibility in those at risk for hereditary pancreatic cancer may have direct applicability to clinical practice in cases with mutations in actionable genes. Future pancreatic cancer predisposition studies should include evaluation of the Fanconi anemia genes.",
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