ATM mutations in patients with hereditary pancreatic cancer |
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Authors: | 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 |
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Affiliation: | Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland, USA. |
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Abstract: | 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. |
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