ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances

摘要

The ataxia-telangiectasia mutated (ATM) gene codifies for a protein critically involved in the cellular response to DNA damage, ATM alterations have been observed in some sporadic lymphoproliferative disorders. The recurrent 11q22-23 deletions found in mantle cell lymphoma (MCL) suggest that ATM could be inactivated in these lymphomas. In this study, ATM gene alterations and protein expression were examined in 20 and 17 MCL tumor specimens, respectively. Previously, these patients had been examined for p53 and p14ARF gene status and analyzed by comparative genomic hybridization. Nine patients had 11q22-23 losses. Eight ATM gene mutations were detected in 7 patients. These alterations were 3 missense mutations in the phosphatidyl-inositol-3 kinase (PI-3K) domain and 5 truncating mutations,including 3 frame-shifts, a nonsense mutation, and a substitution of the initial methionine. All truncating mutations were associated with lack of protein expression. Somatic origin was demonstrated in 3 mutations, whereas one mutation was carried heterozygously in the patient germ line. Chromosomal imbalances were significantly higher in typical MCL with ATM inactivation(7.8 ± 1.3) than in tumors with the wild-type gene (3 ± 1.1) (P= .001). Moreover, tumors with bi-allelic ATM alteration were associated with 3q gains (P = .015) and frequent extranodal involvement (P = .049). ATM gene alterations were not related to the histologic variant of the tumors,p53/p14ARF gene status, survival, or other clinicopathologic features of the patients. These findings indicate that ATM gene mutations in MCL are mainly truncating or missense mutations involving the PI-3K domain,and that may play a role in the pathogenesis of a subset of these tumors with increased numbers of chromosomal imbalances. © 2002 by The American Society of Hematology.