期刊
CANCER DISCOVERY
卷 2, 期 1, 页码 41-46出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-11-0194
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资金
- Lustgarten Foundation for Pancreatic Cancer Research
- Virginia and D. K. Ludwig Fund for Cancer Research
- Sol Goldman Pancreatic Cancer Research Center NIH [CA62924, CA057345, CA123483, CA121113, RO1CA97075]
- Michael Rolfe Pancreatic Cancer Foundation
- Stand Up To Cancer Dream Team
- Entertainment Industry Foundation [SU2C-AACR-DT0509]
- Stringer Foundation
- Joseph L. Rabinowitz Fund for Pancreatic Cancer Research
- Karp Family
- H.H. & M. Metals, Inc.
- Fund for Cancer Research
- NCI [N01-PC-35145, NO1-CN-43302]
Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. SIGNIFICANCE : The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes. Cancer Discovery; 2(1): 41-6. (C) 2011 AACR.
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