ATM mutations in patients with hereditary pancreatic cancer

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.

Figure 1. Pedigrees of familial pancreatic cancer families FPC-A and FPC-B

I. Family FPC-A. Individuals interrogated with whole-genome sequencing. Individuals with an ATM mutation indicated with K2756X. II. Family FPC-B. Individuals interrogated with whole exome sequencing. Individuals an ATM mutation indicated with W57X.

Figure 2. Chromatograms from IV-1 of family FPC-A

I. Peripheral blood lymphocytes of IV-1 demonstrating heterozygosity for the ATM inactivating mutant c.8266A>AT; p.K1756X. II. Laser capture microdissected pancreatic tumor of IV-1 showing loss of heterozygosity with retention of the ATM inactivating mutant c.8266A>T; p.K1756X.