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

Inherited mutations of the ATM gene are responsible for the human autosomal recessive disorder ataxia-telangiectasia (A-T) characterized by pleiotropi c clinical manifestations. ATM mutations are also involved in the developme nt of sporadic human cancers such as T-cell prolymphocytic leukemia and B-c ell chronic lymphocytic leukemia. Little is known, however, on the associat ion of ATM mutations with nonlymphoid malignancy. Here, we analyzed a panel of cell lines derived from human solid tumors for the presence of ATM muta tions. PCR-SSCP analysis of 25 tumor cell lines revealed 50 sequence altera tions in 16 cell lines. The most striking feature was a high frequency of d eletions within the intronic mononucleotide tracts exclusively in the 5 col on tumor cell lines with microsatellite instability, which accounted for 62 % of the sequence alterations observed here. Generation of aberrant splicin g variants (497de122 or 1236de1372) was associated with 2 such intronic del etions at splice acceptor sites preceding ATM exon 8 or exon 12, respective ly. The level of ATM protein was partially depressed in the 3 cell lines wh ere expression of protein-truncating 497de122 transcripts dominated. This i mplies that ATM is a novel mutation target of microsatellite instability wh ere abnormal transcripts are generated indirectly by intronic mutations, wh ich is distinct from the other mutation targets such as the type II TGF-bet a receptor gene or BAX, where exonic repeats are directly affected. Int. J. Cancer 86:262-268, 2000. (C) 2000 Wiley-Liss. Inc.