ATM Mutations in Patients with Hereditary Pancreatic Cancer

作者：Roberts, Nicholas J.; Jiao, Yuchen; Yu, Jun; Kopelovich, Levy; Petersen, Gloria M.; Bondy, Melissa L.; Gallinger, Steven; Schwartz, Ann G.; Syngal, Sapna; Cote, Michele L.; Axilbund, Jennifer; Schulick, Richard; Ali, Syed Z.; Eshleman, James R.; Velculescu, Victor E.; Goggins, Michael; Vogelstein, Bert; Papadopoulos, Nickolas; Hruban, Ralph H.; Kinzler, Kenneth W.; Klein, Alison P.^*

来源：Cancer Discovery, 2012, 2(1): 41-46.

DOI：10.1158/2159-8290.CD-11-0194

• ATAXIA-TELANGIECTASIA
• BREAST-CANCER
• GENE
• IDENTIFICATION
• HETEROZYGOTES
• PHENOTYPES
• FAMILIES
• TUMORS
• ONSET

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.

• 出版日期2012-1