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

Xiaohong R. Yang, Melissa Rotunno, Yanzi Xiao, Christian Ingvar, Hildur Helgadottir, Lorenza Pastorino, Remco van Doorn, Hunter Bennett, Cole Graham, Joshua N. Sampson, Michael Malasky, Aurelie Vogt, Bin Zhu, Giovanna Bianchi-Scarra, William Bruno, Paola Queirolo, Giuseppe Fornarini, Johan Hansson, Rainer Tuominen, Laurie BurdettBelynda Hicks, Amy Hutchinson, Kristine Jones, Meredith Yeager, Stephen J. Chanock, Maria Teresa Landi, Veronica Höiom, Håkan Olsson, Nelleke Gruis, Paola Ghiorzo, Margaret A. Tucker, Alisa M. Goldstein

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalHuman Genetics
DOIs
Publication statusAccepted/In press - Jul 23 2016

    Fingerprint

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Yang, X. R., Rotunno, M., Xiao, Y., Ingvar, C., Helgadottir, H., Pastorino, L., van Doorn, R., Bennett, H., Graham, C., Sampson, J. N., Malasky, M., Vogt, A., Zhu, B., Bianchi-Scarra, G., Bruno, W., Queirolo, P., Fornarini, G., Hansson, J., Tuominen, R., ... Goldstein, A. M. (Accepted/In press). 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. Human Genetics, 1-9. https://doi.org/10.1007/s00439-016-1715-1