Germ-Line ATM Gene Alterations Are Associated with Susceptibility to Sporadic T-Cell Acute Lymphoblastic Leukemia in Children

Ella Liberzon, Smadar Avigad, Batia Stark, Julia Zilberstein, Laurence Freedman, Malka Gorfine, Herzel Gavriel, Ian J. Cohen, Yacov Goshen, Isaac Yaniv, Rina Zaizov

Research output: Contribution to journalArticlepeer-review


A major feature of ataxia-telangiectasia (A-T) is an increased risk of cancer, particularly of lymphoid malignancies. We studied ATM gene involvement in leukemic cells derived from 39 pediatric T-cell acute lymphoblastic leukemias (ALLs). Two types of sequence changes-truncating and missense-were identified in 8 T-cell ALL samples: 3 truncating changes, all previously identified in A-T (R35X, -30del215, 2284delCT), and 3 missense variants (V410A, F582L, F1463C) were found, none associated with loss of heterozygosity (LOH). In all patients studied, the mutation was present in the germ-line. A-T carriers, defined by the finding of truncating mutations, were found to be 12.9 times more frequent than in the normal population (P = 0.004). A normally ethnically matched population was screened for the 3 missense variants, and their frequency was significantly more prevalent (4.9-fold excess) than in the normal population (P = 0.03). Our data suggest there is some evidence of an association between missense alterations in the ATM gene and T-cell ALL. A significant difference in the mean age at diagnosis of T-cell ALL was noted between patients harboring an ATM sequence change and those with no change, 5.4 years and 9.7 years, respectively (P = 0.001). No ATM alterations were identified in relapse samples, indicating that ATM does not play a role in disease progression. The high prevalence of germ-line truncating and missense ATM gene alterations among children with sporadic T-cell ALL suggests an association with susceptibility to T-cell acute leukemia and supports the model of predisposition to cancer in A-T heterozygotes.

Original languageEnglish
Pages (from-to)161-166
Number of pages6
JournalGenes Chromosomes and Cancer
Issue number2
StatePublished - Feb 2004


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