MUTATIONS OF MITOTIC CHECKPOINT GENES IN HUMAN CANCERS

Genetic instability was one of the first characteristics to be postula ted to underlie neoplasia(1-3). Such genetic instability occurs in two different forms. In a small fraction of colorectal and some other can cers, defective repair of mismatched bases results in an increased mut ation rate at the nucleotide level and consequent widespread microsate llite instability(4-7). In most colorectal cancers, and probably in ma ny other cancer types, a chromosomal instability (GIN) leading to an a bnormal chromosome number (aneuploidy) is observed(8). The physiologic al and molecular bases of this pervasive abnormality are unknown. Here we show that CIN is consistently associated with the loss of function of a mitotic checkpoint, Moreover, in some cancers displaying CIN the loss of this checkpoint was associated with the mutational inactivati on of a human homologue of the yeast BUB1 gene; BUB1 controls mitotic checkpoints and chromosome segregation in yeast, The normal mitotic ch eckpoints of cells displaying microsatellite instability become defect ive upon transfer of mutant hBUB1 alleles from either of two CIN cance rs.