Aneuploidy — gains or losses of whole chromosomes — is a common feature of tumours, but it is not clear how this defect occurs, or whether it is a cause or simply a by-product of transformation. Sandra Hanks et al. report that mutations in the spindle-checkpoint gene BUB1B cause aneuploidy and contribute to an inherited cancer-predisposition syndrome.

The mitotic-spindle checkpoint is a surveillance mechanism that maintains the correct chromosome number during cell division. A large number of proteins, including members of the BUB and MAD family, regulate this process, delaying anaphase until the kinetochores of each chromosome pair have successfully attached to the spindle.

In a search for genetic defects that might cause mosaic variegated aneuploidy (MVA), a recessive condition characterized by aneuploidies and other chromosome defects, Hanks et al. identified mutations in both BUB1B alleles in five out of eight families with a history of this rare disease. MVA causes several developmental defects as well as a high risk of malignancy, with rhabdomyosarcoma, Wilms' tumour and leukaemia reported in several cases. Five individuals who were found to carry biallelic truncating and missense mutations in BUB1B had phenotypes typical of MVA, and two of these cases developed cancer. No such mutations have been detected in tumour cells collected from patients with other types of cancer, or from normal cell samples.

In mice, reduced expression of BUB1R, the protein encoded by BUB1B, results in defective spindle-checkpoint activation, aneuploidy, and predisposition to lung and colon cancers. In some human cancers, BUB1B has been shown to be epigenetically downregulated. So, aneuploidy, when caused by a functional disruption of the mitotic-spindle checkpoint, seems to be an important contributing factor to human cancer. Further studies will reveal whether defects in other spindle-checkpoint genes also contribute to aneuploidy-associated cancers.