Aneuploidy Drives a Mutator Phenotype in Cancer

An abnormal chromosome number alone can induce mutations that may promote cancer initiation or progression. The association of chromosomal abnormalities with cancer—including chromosome translocations, deletions, amplifications, and inappropriate numbers of chromosomes (aneuploidy)—has been known for more than a century. Even karyotypically stable cancers are genetically abnormal because of high frequencies of point mutations. Despite our current understanding of cancer genomes, it has been difficult to determine whether many genetic abnormalities are a cause or consequence of carcinogenesis. Increased missegregation of whole chromosomes prior to the final steps of cell division (mitosis) generates aneuploidy and can promote tumorigenesis in some genetic contexts in mice (1), as the German biologist Theodor Boveri initially proposed more than 100 years ago. Two papers in this issue, by Sheltzer et al. (2) on page 1026 and Solomon et al. (3) on page 1039, show that aneuploidy enhances genetic recombination and defective DNA damage repair, thereby providing a mechanistic link between aneuploidy and genomic instability.