title: Aberrant splicing of the ATM gene associated with shortening of the intronic mononucleotide tract in human colon tumor cell lines: a novel mutation target of microsatellite instability.
abstract: Inherited mutations of the ATM gene are responsible for the human autosomal recessive disorder ataxia-telangiectasia (A-T) characterized by pleiotropic clinical manifestations. ATM mutations are also involved in the development of sporadic human cancers such as T-cell prolymphocytic leukemia and B-cell chronic lymphocytic leukemia. Little is known, however, on the association of ATM mutations with non-lymphoid malignancy. Here, we analyzed a panel of cell lines derived from human solid tumors for the presence of ATM mutations. PCR-SSCP analysis of 25 tumor cell lines revealed 50 sequence alterations in 16 cell lines. The most striking feature was a high frequency of deletions within the intronic mononucleotide tracts exclusively in the 5 colon tumor cell lines with microsatellite instability, which accounted for 62% of the sequence alterations observed here. Generation of aberrant splicing variants (497del22 or 1236del372) was associated with 2 such intronic deletions at splice acceptor sites preceding ATM exon 8 or exon 12, respectively. The level of ATM protein was partially depressed in the 3 cell lines where expression of protein-truncating 497del22 transcripts dominated. This implies that ATM is a novel mutation target of microsatellite instability where abnormal transcripts are generated indirectly by intronic mutations, which is distinct from the other mutation targets such as the type II TGF-beta receptor gene or BAX, where exonic repeats are directly affected.
authors.affiliation: Department of Radiological Sciences and Technology, Hiroshima Prefectural College of Health and Welfare, Hiroshima, Japan. ezima@hpc.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Ejima
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: M S
authors.initials: MS
authors.lastname: Sasaki
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000235:genetics*; D017931:DNA Primers; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D006801:Humans; D007438:Introns; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases