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

Alyssa L. Smith, Najmeh Alirezaie, Ashton Connor, Michelle Chan-Seng-Yue, Robert Grant, Iris Selander, Claire Bascuñana, Ayelet Borgida, Anita Hall, Thomas Whelan, Spring Holter, Treasa McPherson, Sean Cleary, Gloria M Petersen, Atilla Omeroglu, Emmanouil Saloustros, John McPherson, Lincoln D. Stein, William D. Foulkes, Jacek MajewskiSteven Gallinger, George Zogopoulos

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)302-312
Number of pages11
JournalCancer Letters
Volume370
Issue number2
DOIs
StatePublished - Jan 28 2016

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Keywords

  • DNA repair genes
  • Exome sequencing
  • Familial pancreatic cancer
  • Pancreatic adenocarcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Smith, A. L., Alirezaie, N., Connor, A., Chan-Seng-Yue, M., Grant, R., Selander, I., Bascuñana, C., Borgida, A., Hall, A., Whelan, T., Holter, S., McPherson, T., Cleary, S., Petersen, G. M., Omeroglu, A., Saloustros, E., McPherson, J., Stein, L. D., Foulkes, W. D., ... Zogopoulos, G. (2016). Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer. Cancer Letters, 370(2), 302-312. https://doi.org/10.1016/j.canlet.2015.10.030