Haploinsufficient Gene Selection in Cancer

Cell proliferation experiments suggest that cancer can gain an advantage by partially inactivating several genes simultaneously with single deletion events. Cancer is caused when normal signals regulating cell growth are disrupted by mutations in cancer genes, which are now known to number in the hundreds (1). These “driver” mutations are generally localized, only affecting the implicated cancer genes to produce a clear functional response that drives tumorigenesis. Cancer genomes, however, harbor thousands of mutations (2–4), only a handful of which affect cancer genes. The majority are “passenger” mutations that are likely to have little or no functional consequence. These mutations exhibit great diversity in character and some can affect large genomic regions containing many genes. This raises the question of whether such large genomic assaults can be entirely passenger in nature. On page 104 of this issue, Solimini et al. (5) study one such common class of mutation known as hemizygous deletion and demonstrate that the cumulative response from the genes affected is sufficient to promote tumorigenesis.