title: Germ-line ATM gene alterations are associated with susceptibility to sporadic T-cell acute lymphoblastic leukemia in children.
abstract: 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.
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Liberzon
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.forename: Batia
authors.initials: B
authors.lastname: Stark
authors.forename: Julia
authors.initials: J
authors.lastname: Zilberstein
authors.forename: Laurence
authors.initials: L
authors.lastname: Freedman
authors.forename: Malka
authors.initials: M
authors.lastname: Gorfine
authors.forename: Herzel
authors.initials: H
authors.lastname: Gavriel
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Cohen
authors.forename: Yacov
authors.initials: Y
authors.lastname: Goshen
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Rina
authors.initials: R
authors.lastname: Zaizov
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases