Mantle cell lymphoma is characterized by inactivation of the ATM gene

In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Recently, however, deletion of the ch romosomal 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 (atax ia 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 pote ntial 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 analysi s of reverse transcription-PCR-amplified mRNA and subsequent DNA sequencing . In all seven cases containing a deletion of one ATM allele, a point mutat ion in the remaining allele was detected, which resulted in aberrant transc ript splicing, truncation, or alteration of the protein. In addition, biall elic A TIW mutations were identified in two MCLs that did not contain 11q d eletions. Interestingly, in three cases analyzed, the ATM mutations detecte d in the tumor cells were not present in nonmalignant cells, demonstrating their somatic rather than germ-line origin. The inactivation of both allele s of the ATM gene by deletion and deleterious point mutation in the majorit y of cases analyzed indicates that ATM plays a role in the initiation and/o r progression of MCL.