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Nature 392, 300-303 (19 March 1998) | doi:10.1038/32688; Accepted 6 February 1998

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Mutations of mitotic checkpoint genes in human cancers

Daniel P. Cahill1,2, Christoph Lengauer1,2, Jian Yu1, Gregory J. Riggins1, James K. V. Willson3, Sanford D. Markowitz3, Kenneth W. Kinzler1 & Bert Vogelstein1

  1. The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 424 North Bond Street, Baltimore, Maryland 21231, USA
  2. Department of Medicine and Ireland Cancer Center, Case Western Reserve University and The Howard Hughes Medical Institute, Cleveland, Ohio 44106, USA
  3. These authors contributed equally to this study.

Correspondence to: Christoph Lengauer1,2 Correspondence and requests for materials should be addressed to C.L. (Email: lengauer@welchlink.welch.jhu.edu). The accession numbers for hBUB1 and hBUBR1 are AF046078 and AF046079, respectively.

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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.

  1. The Johns Hopkins Oncology Center, Program in Human Genetics, and The Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 424 North Bond Street, Baltimore, Maryland 21231, USA
  2. Department of Medicine and Ireland Cancer Center, Case Western Reserve University and The Howard Hughes Medical Institute, Cleveland, Ohio 44106, USA
  3. These authors contributed equally to this study.

Correspondence to: Christoph Lengauer1,2 Correspondence and requests for materials should be addressed to C.L. (Email: lengauer@welchlink.welch.jhu.edu). The accession numbers for hBUB1 and hBUBR1 are AF046078 and AF046079, respectively.