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

作者：Yang Xiaohong R; Rotunno Melissa; Xiao Yanzi; Ingvar Christian; Helgadottir Hildur; Pastorino Lorenza; van Doorn Remco; Bennett Hunter; Graham Cole; Sampson Joshua N; Malasky Michael; Vogt Aurelie; Zhu Bin; Bianchi Scarra Giovanna; Bruno William; Queirolo Paola; Fornarini Giuseppe; Hansson Johan; Tuominen Rainer; Burdett Laurie; Hicks Belynda; Hutchinson Amy; Jones Kristine; Yeager Meredith; Chanock Stephen J; Landi Maria Teresa; Hoiom Veronica; Olsson Hakan

来源：Human Genetics, 2016, 135(11): 1241-1249.

DOI：10.1007/s00439-016-1715-1

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.

• 出版日期2016-11
• 单位NIH