Specific clones of spontaneously evolving karyotypes generate individuality of cancers

Abstract Several researchers, including us, have recently proposed that specific karyotypes, rather than specific mutations, generate the “biochemical individuality” of cancers, defined by individual growth rates, metabolisms, drug-resistances, metastases and cell morphologies. According to our theory, independent karyotypic evolutions generate cancers, much like new phylogenetic species. To allow such evolutions in the lifetime of an organism, the normal karyotype must be destabilized, but not the genes. The karyotype is destabilized by aneuploidy, because aneuploidy unbalances conserved teams of proteins that segregate, synthesize and repair chromosomes. And aneuploidy is induced either by carcinogens or spontaneously. Here, we tested this theory using a new system that virtually excludes spontaneous mutation. In this sytem, 50% of normal human muscle cells became aneuploid and 5 per 106 formed foci of transformed Mu6 cells - only 2 months after transfection with 6 virus-activated cellular genes. Analyses of 10 foci revealed: (1) clonal karyotypes, consisting of one or more stemlines of spontaneously evolving aneuploidies and some non-clonal aneuploidies, and (2) individual phenotypes, such as cell morphologies, growth rates and intrinsic resistance to cytosine arabinoside, shared by 5 foci with a common stemline. Due to the short preneoplastic latencies of Mu6 cells several non-clonal precursors of focus-specific, aneuploid karyotypes were detectable before focus formation. Chemical carcinogens were also found to induce tumors with clonally evolving stemlines in Chinese hamsters. We conclude that specific clones of spontaneously evolving karyotypes, rather than specific mutations, generate the individuality of cancers. This answers the age-old question, why even cancers of the same kind do not have consistent karyotypes.