@article{6cc9dda9eb4c493b823e74bcfec7b7d8,
title = "Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer",
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",
author = "Smith, {Alyssa L.} and Najmeh Alirezaie and Ashton Connor and Michelle Chan-Seng-Yue and Robert Grant and Iris Selander and Claire Bascu{\~n}ana and Ayelet Borgida and Anita Hall and Thomas Whelan and Spring Holter and Treasa McPherson and Sean Cleary and Petersen, {Gloria M.} and Atilla Omeroglu and Emmanouil Saloustros and John McPherson and Stein, {Lincoln D.} and Foulkes, {William D.} and Jacek Majewski and Steven Gallinger and George Zogopoulos",
note = "Funding Information: This work was funded by the Cancer Research Society and the National Pancreatic Cancer Canada Foundation (to G.Z.), the Research Institute McGill University Health Centre (to G.Z.), the Department of Oncology of the McGill University Health Centre (to G.Z.), the Goodman Cancer Research Centre and the McGill University Innovation Centre (to G.Z.), the National Pancreatic Cancer Canada Foundation (to S.G.), the W. Garfield Weston Foundation (to S.G.), Ontario Institute for Cancer Research (to S.G., J.Mc., L.S.) and the National Cancer Institute /National Institutes of Health ( R01CA97075 , to S.G., G.P.). A.L.S. is supported by a Cedars Cancer Institute Fellowship. G.Z. is a clinical research scholar of the Fonds de Recherche du Qu{\'e}bec – Sant{\'e} . We would like to thank the hepato-pancreato-biliary and pathology services of the McGill University Health Centre and the University Health Network for their support with patient enrollment and biospecimen collection. We would also like to acknowledge the staff of the Biospecimen Repository of Mount Sinai Hospital for their technical support. Publisher Copyright: {\textcopyright} 2015 Elsevier Ireland Ltd.",
year = "2016",
month = jan,
day = "28",
doi = "10.1016/j.canlet.2015.10.030",
language = "English (US)",
volume = "370",
pages = "302--312",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "2",
}