On the karyotypic origin and evolution of cancer cells.

Cancers have clonal, aneuploid karyotypes that evolve ever more malignant phenotypes spontaneously. 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 from mass cultures of human cells within a few months 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 immunodeficient mice were variants of those of the input clones. The karyotypes 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 like conventional carcinogens, but more effectively because the oncogenes are integrated into the genome. Since aneuploidy destabilizes the karyotype, such cells evolve new, cancer-specific karyotypes spontaneously, much like new species. Because individual karyotypes of tumorigenic clones correlate and coevolve with individual phenotypes, we conclude that specific karyotypes as a whole are the genomes of cancer cells. Owing to the flexibility of their aneuploid karyotypes, cancers evolve at rates that are roughly proportional to their degrees of aneuploidy. In sum, genomes consisting of individual and flexible karyotypes explain the characteristic individuality, stability, and flexibility of cancers.