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.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

Under agreements between the Johns Hopkins University, Inostics, PGDx and Qiagen, N.P., B.V., K.W.K. and V.E.V are entitled to a share of the royalties received by the University on sales of products related to genes and technologies described in this manuscript. N.P., B.V., K.W.K. and V.E.V are a co-founders of Inostics and Personal Genome Diagnostics are members of their Scientific Advisory Boards, and own stock in Inostics and PGDx, which is subject to certain restrictions under Johns Hopkins University policy. The terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Figures

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.