Mutations of mitotic checkpoint genes in human cancers

Daniel P. Cahill, Christoph Lengauer (), Jian Yu, Gregory J. Riggins, James K. V. Willson, Sanford D. Markowitz, Kenneth W. Kinzler and Bert Vogelstein
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Daniel P. Cahill: The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Christoph Lengauer: The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Jian Yu: The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Gregory J. Riggins: The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
James K. V. Willson: Case Western Reserve University and The Howard Hughes Medical Institute
Sanford D. Markowitz: Case Western Reserve University and The Howard Hughes Medical Institute
Kenneth W. Kinzler: The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Bert Vogelstein: The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine

Nature, 1998, vol. 392, issue 6673, 300-303

Abstract: Abstract Genetic instability was one of the first characteristics to be postulated to underlie neoplasia1,2,3. Such genetic instability occurs in two different forms. In a small fraction of colorectal and some other cancers, defective repair of mismatched bases results in an increased mutation rate at the nucleotide level and consequent widespread microsatellite instability4,5,6,7. In most colorectal cancers, and probably in many other cancer types, a chromosomal instability (CIN) leading to an abnormal chromosome number (aneuploidy) is observed8. The physiological 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 inactivation of a human homologue of the yeast BUB1 gene; BUB1 controls mitotic checkpoints and chromosome segregation in yeast. The normal mitotic checkpoints of cells displaying microsatellite instability become defective upon transfer of mutant hBUB1 alleles from either of two CIN cancers.

Date: 1998
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DOI: 10.1038/32688

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