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.
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Acknowledgments
We are indebted to the participating families, whose generosity and cooperation have made this study possible. We acknowledge the research nurse contributions to this work that were made by Virginia Pichler (NCI), Deborah Zametkin (NCI), Mary Fraser (NCI), and Anita Zander (Lund). We wish to thank Dr. Chiara Baldo from the Galliera Genetic Bank-Network of Telethon Genetic Biobanks (Project No. GTB12001, Telethon, Italy) for providing patients’ lymphoblastoid cell lines. We acknowledge the contribution of members of the NCI DCEG Cancer Sequencing Working Group: Lynn R. Goldin, Mary L. McMaster, Neil E. Caporaso, Bari Ballew, Sharon Savage, Mark H. Greene, Allan Hildesheim, Nan Hu, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, and Guoqin Yu and members of the NCI DCEG Cancer Genomics Research Laboratory: Sarah Bass, Joseph Boland, Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Sally Larson, Kerry Lashley, Hyo Jung Lee, Wen Luo, Michelle Manning, Jason Mitchell, David Roberson, Mingyi Wang. We acknowledge the contributions of the Genoa Pancreatic Cancer Study Group: Virginia Andreotti, Claudia Martinuzzi, Luca Mastracci, Federica Grillo, Vincenzo Savarino, Pietro Dulbecco, Stefania Sciallero, Francesco Spagnolo, Virginia Picasso, Franco DeCian, Barbara Pasini, Paola Ogliara, Daniela Turchetti, Elena Sala.
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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).
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Yang, X.R., Rotunno, M., Xiao, Y. et al. 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. Hum Genet 135, 1241–1249 (2016). https://doi.org/10.1007/s00439-016-1715-1
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DOI: https://doi.org/10.1007/s00439-016-1715-1