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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
Author(s) -
Ejima Yosuke,
Yang Lichun,
Sasaki Masao S.
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(20000415)86:2<262::aid-ijc17>3.0.co;2-i
Subject(s) - biology , microsatellite instability , exon , mutation , microbiology and biotechnology , rna splicing , genetics , cancer research , gene , chronic lymphocytic leukemia , leukemia , microsatellite , allele , rna
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‐β receptor gene or BAX, where exonic repeats are directly affected. Int. J. Cancer 86:262–268, 2000. © 2000 Wiley‐Liss, Inc.