ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell lymphoma

Abstract

The ATM serine-threonine kinase plays a central role in the cellular response to DNA damage. Germ-line mutations in the ATM gene cause ataxia-telangiectasia (A-T), a multisystem disorder associated with predisposition to lymphoma and acute leukemia. Moreover, somatic ATM mutations have been identified in T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia. In this study, the entire ATM coding sequence was examined in genomic DNA from 120 lymphoid neoplasms. Novel mutations and mutations implicated in cancer and/or A-T were found in 9 of 45 diffuse large B-cell lymphomas (DLBCLs), 2 of 24 follicular lymphomas, and 1 of 27 adult acute lymphoblastic leukemias, whereas no such mutations were detected among 24 peripheral T-cell lymphomas. The mutational spectrum consisted of 2 nonsense mutations, 1 mutation affecting RNA splicing, and 10 missense variants. Most of these mutations were associated with loss or mutation of the paired ATM allele, consistent with biallelic inactivation of ATM. Of the 9 DLBCLs with ATM mutations, 7 also carried TP53 mutations and/or deletions of the INK4a/ARF locus (P =.003). The ATM 735C>T substitution previously considered a rare normal variant was found to be 5.6 times more frequent in individuals with DLBCL than in random individuals (P =.026), suggesting that it may predispose to B-cell lymphoma. Our data suggest that ATM mutations contribute to the development of DLBCL, and that ATM and the ARF-p53 tumor suppressor pathway may cooperate in the pathogenesis of this malignancy.