title: Mutation of the ATM gene is not involved in the pathogenesis of either follicle center lymphoma or its transformation to higher-grade lymphoma.
abstract: Loss of function of the ataxia-telangiectasia mutated (ATM) gene, located on human chromosome 11q22-23, is the cause of ataxia-telangiectasia (A-T), which is associated with an extremely high risk for lymphoma. Abnormalities in 11q22-23, including deletions and mutations of the ATM gene, have been reported in T-cell prolymphocytic leukemias, B-CLL and in mantle cell lymphoma. In a survey of gene expression in follicle center lymphomas (FCL) and diffuse large B-cell lymphomas (DLBCL), almost all FCL expressed significant levels of ATM and the majority of DLBCL expressed low levels of ATM. This finding raised the possibility that the transformation of some FCL to DLBCL might be associated with inactivation of the ATM gene. Therefore, we analyzed biopsy specimens of 17 patients with FCL obtained at the time of diagnosis, four subsequent biopsies obtained at the time of FCL relapse and seven subsequent biopsies at the time of transformation to DLBCL. A comprehensive analysis of the ATM gene was performed by denaturing high performance liquid chromatography and sequencing. The analysis covered all of the 66 exons including the 9168 base pairs of ATM coding sequence as well as 16,676 base pairs of non-coding sequence. Twenty-eight known polymorphisms and rare sequence variants were observed, but no classic A-T mutations were detected. In 11 tumors, both tumor B-cells and normal T-cells were sorted for separate examination, and in each case, polymorphisms and rare variants were present in both tumor and normal cells. No new ATM gene mutations were associated with transformation from FCL to DLBCL. Thus, ATM gene mutations do not play a pivotal role either in the pathogenesis of FCL or in its transformation to DLBCL.
authors.affiliation: Department of Medicine, Stanford University Medical Center, CA 94305-5151, USA.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.forename: Yvonne R
authors.initials: YR
authors.lastname: Thorstenson
authors.forename: Tierney L
authors.initials: TL
authors.lastname: Wayne
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
authors.forename: Gilbert
authors.initials: G
authors.lastname: Chu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006239:Haplotypes; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D008228:Lymphoma, Non-Hodgkin / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; 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