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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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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