Aneuploidy versus gene mutation as cause of cancer [Review]

摘要

The mutagenic ranges of aneuploidy, an abnormal number of chromosomes, and gene mutation are analyzed for their abilities to cause the dominant phenotypes of cancer. In the cell, activating gene mutations are buffered because virtually all gene products are kinetically linked into biochemical assembly lines and thus functionally controlled by upstream and downstream enzymes working at their native rates. Inactivating mutations are also buffered, because (i) they are oversupplied with substrate from unmutated upstream enzymes, (ii) are functionally complemented by a second un-mutated allele, and (iii) because in the cell all enzymes work far below saturation. Therefore, gene mutations are typically recessive and thus unable to generate dominant phenotypes. The argument, that all hypothetically carcinogenic gene mutations are exceptional dominants, is hard to reconcile with their failure to transform cells in vitro and in transgenic animals. By contrast,. numerical variations of chromosomes, encoding complete biochemical assembly lines, inevitably generate dominant phenotypes, consider the chromosomes that determine sex or Down syndrome., Thus aneuploidy above an as yet poorly defined threshold emerges as the only plausible mutation to cause the dominant phenotypes of cancer. The aneuploidy hypothesis also explains the exceedingly long latent periods, years to decades, between carcinogen and carcinogenesis. Since aneuploidy destabilizes mitosis by unbalancing mitosis proteins, it catalyzes karyotype evolution that eventually generates carcinogenic karyotypes. Three predictions of the hypothesis have been confirmed experimentally, (i) that human cancer cells, reportedly generated by 'three defined genetic elements', are aneuploid, (ii) that an 'immortal' liver cell line, reportedly safe for human transplantation, is aneuploid and thus preneoplastic, (iii) that the high mutation rates of cancer cells to drug and multidrug-resistance are due to chromosome reassortments.