Journal
HUMAN GENETICS
Volume 135, Issue 11, Pages 1241-1249Publisher
SPRINGER
DOI: 10.1007/s00439-016-1715-1
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Funding
- Intramural Research Program of the National Cancer Institute, the National Institutes of Health, the Division of Cancer Epidemiology and Genetics
- Swedish Cancer Society
- Kamprad Foundation
- Gunnar Nilsson Foundation
- ERC [294576]
- Swedish Medical Research Council
- Radiumhemmets research funds
- Stockholm County Council (ALF-project)
- Karolinska Institutet Research funds
- Paulsson Trust (Lund)
- AIRC [IG 15460]
- Italian Ministry of Health
- Dutch Cancer Society [UL 2012-5489]
- European Research Council (ERC) [294576] Funding Source: European Research Council (ERC)
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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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