@article{262eb92c3f6246fdb6e925ebc216ad6d,
title = "Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations",
abstract = "The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A− cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A− PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A− PC patients. Further, nine CDKN2A+ and four CDKN2A− PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A− PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A− PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.",
author = "Yang, {Xiaohong R.} and Melissa Rotunno and Yanzi Xiao and Christian Ingvar and Hildur Helgadottir and Lorenza Pastorino and {van Doorn}, Remco and Hunter Bennett and Cole Graham and Sampson, {Joshua N.} and Michael Malasky and Aurelie Vogt and Bin Zhu and Giovanna Bianchi-Scarra and William Bruno and Paola Queirolo and Giuseppe Fornarini and Johan Hansson and Rainer Tuominen and Laurie Burdett and Belynda Hicks and Amy Hutchinson and Kristine Jones and Meredith Yeager and Chanock, {Stephen J.} and Landi, {Maria Teresa} and Veronica H{\"o}iom and H{\aa}kan Olsson and Nelleke Gruis and Paola Ghiorzo and Tucker, {Margaret A.} and Goldstein, {Alisa M.}",
note = "Funding Information: This work was supported by the Intramural Research Program of the National Cancer Institute, the National Institutes of Health, the Division of Cancer Epidemiology and Genetics. This work was also supported in part by the Swedish Cancer Society, Kamprad Foundation, Gunnar Nilsson Foundation and the ERC advanced Grant 294576-risk factors cancer; the Swedish Medical Research Council, the Swedish Cancer Society, Radiumhemmets research funds, the Stockholm County Council (ALF-project), Karolinska Institutet Research funds; The Paulsson Trust (Lund); AIRC IG 15460 to PG, Italian Ministry of Health 5 × 1000 to IRCCS AOU San Martino-IST to PG and GBS; the work of NAG and RvD was in part supported by the Dutch Cancer Society (UL 2012-5489). Publisher Copyright: {\textcopyright} 2016, Springer-Verlag Berlin Heidelberg (otside the USA).",
year = "2016",
month = nov,
day = "1",
doi = "10.1007/s00439-016-1715-1",
language = "English (US)",
volume = "135",
pages = "1241--1249",
journal = "Human genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "11",
}