On the karyotypic origin and evolution of cancer cells

Abstract Cancers have clonal, aneuploid karyotypes that evolve ever more malignant phenotypes spontane-ously. Because these facts are hard to explain by conventional mutation theory, we propose here a karyotypic cancer theory. According to this theory, carcinogens initiate carcinogenesis by inducing random aneuploidy. Aneuploidy then catalyzes karyotypic evolutions, because it destabilizes the karyotype by unbalancing teams of proteins that segregate, synthesize, and repair chromosomes. Sporadically, such evolutions generate new cancer-causing karyotypes, which are stabilized within narrow limits against the inherent instability of aneuploidy by selection for oncogenic function. Here we have tested this theory prospectively by analyzing the karyotypes of distinct tumorigenic clones, which arose frommass cultures of human cells within a fewmonths after transfection with artificially activated oncogenes. All clones from the same parental cells had individual, ‘‘near-clonal’ ’ karyotypes and phenotypes, although the parental oncogenes were identical. The karyotypes of distinct tumors formed by a given clone in immunodeficientmicewerevariants of those of the input clones. The karyo-types of tumorigenic clones also evolved on passages in vitro, in which they acquired either enhanced tumorigenicity spontaneously or resistance against methotrexate upon selection. We conclude that activated oncogenes initiate carcinogenesis indirectly by inducing random aneuploidy, much lik