title: Mantle cell lymphoma is characterized by inactivation of the ATM gene.
abstract: In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Recently, however, deletion of the chromosomal region 11q22-q23 has been identified as a frequent event in this type of cancer, indicating the existence of a pathogenically relevant tumor suppressor gene in this region. The deleted segment contains the ATM (ataxia telangiectasia mutated) gene. ATM is an interesting candidate as a tumor suppressor gene because constitutive inactivation of the gene predisposes ataxia telangiectasia patients to lymphoid malignancies. To assess the potential involvement of the gene in MCL lymphomagenesis, we performed mutation analysis of ATM in 12 sporadic cases of MCL, 7 of them with a deletion of one ATM gene copy, by using single-strand conformation polymorphism analysis of reverse transcription-PCR-amplified mRNA and subsequent DNA sequencing. In all seven cases containing a deletion of one ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, truncation, or alteration of the protein. In addition, biallelic ATM mutations were identified in two MCLs that did not contain 11q deletions. Interestingly, in three cases analyzed, the ATM mutations detected in the tumor cells were not present in nonmalignant cells, demonstrating their somatic rather than germ-line origin. The inactivation of both alleles of the ATM gene by deletion and deleterious point mutation in the majority of cases analyzed indicates that ATM plays a role in the initiation and/or progression of MCL.
authors.affiliation: Abteilung "Organisation komplexer Genome," Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schaffner
authors.forename: I
authors.initials: I
authors.lastname: Idler
authors.forename: S
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.forename: P
authors.initials: P
authors.lastname: Lichter
mesh_terms: D000483:Alleles; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014178:Translocation, Genetic; 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