Aneuploidy versus gene mutation as cause of cancer

The mutagenic ranges of aneuploidy, an abnormal number of chromosomes, and gene mutation are analyzed for their abilities to cause the dominant phenot ypes of cancer. In the cell, activating gene mutations are buffered because virtually all gene products are kinetically linked into biochemical assemb ly lines and thus functionally controlled by upstream and downstream enzyme s working at their native rates. Inactivating mutations are also buffered, because (i) they are oversupplied with substrate from unmutated upstream en zymes, (ii) are functionally complemented by a second un-mutated allele, an d (iii) because in the cell all enzymes work far below saturation. Therefor e, gene mutations are typically recessive and thus unable to generate domin ant phenotypes. The argument, that all hypothetically carcinogenic gene mut ations are exceptional dominants, is hard to reconcile with their failure t o transform cells in vitro and in transgenic animals. By contrast,. numeric al variations of chromosomes, encoding complete biochemical assembly lines, inevitably generate dominant phenotypes, consider the chromosomes that det ermine sex or Down syndrome., Thus aneuploidy above an as yet poorly define d threshold emerges as the only plausible mutation to cause the dominant ph enotypes of cancer. The aneuploidy hypothesis also explains the exceedingly long latent periods, years to decades, between carcinogen and carcinogenes is. Since aneuploidy destabilizes mitosis by unbalancing mitosis proteins, it catalyzes karyotype evolution that eventually generates carcinogenic kar yotypes. Three predictions of the hypothesis have been confirmed experiment ally, (i) that human cancer cells, reportedly generated by 'three defined g enetic elements', are aneuploid, (ii) that an 'immortal' liver cell line, r eportedly safe for human transplantation, is aneuploid and thus preneoplast ic, (iii) that the high mutation rates of cancer cells to drug and multidru g-resistance are due to chromosome reassortments.