Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer

Cancer Lett. 2016 Jan 28;370(2):302-12. doi: 10.1016/j.canlet.2015.10.030. Epub 2015 Nov 3.

Abstract

The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.

Keywords: DNA repair genes; Exome sequencing; Familial pancreatic cancer; Pancreatic adenocarcinoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology
  • DNA Repair / genetics*
  • Exome*
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • NIMA-Related Kinase 1
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / mortality
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology
  • Risk Factors
  • Sequence Analysis, DNA

Substances

  • Cell Cycle Proteins
  • NEK1 protein, human
  • NIMA-Related Kinase 1
  • Protein-Serine-Threonine Kinases