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Mutations of mitotic checkpoint genes in human cancers

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.

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Figure 1: Analysis of the cell cycle of MIN and CIN cells.
Figure 2: Mitotic indices and DNA synthesis in MIN and CIN cells.
Figure 3: Sequence analysis of human BUB1 genes.
Figure 4: The hBUB1 expression system.
Figure 5: Effects of hBUB1 expression.

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Acknowledgements

We thank S. Laken for assistance with the microdissection of tumours, J. Flook for assistance with flow cytometry, and T. Henn for assistance with FISH. This work was supported by the Clayton Fund and grants from the NIH. B.V. and S.D.M. are Investigators of the Howard Hughes Medical Institute.

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Correspondence to Christoph Lengauer.

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Cahill, D., Lengauer, C., Yu, J. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998). https://doi.org/10.1038/32688

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