GENETIC INSTABILITY OF CANCER-CELLS IS PROPORTIONAL TO THEIR DEGREE OF ANEUPLOIDY

Genetic and phenotypic instability are hallmarks of cancer cells, but their cause is not clear, The leading hypothesis suggests that a poorl y defined gene mutation generates genetic instability and that some of many subsequent mutations then cause cancer. Here we investigate the hypothesis that genetic instability of cancer cells is caused by aneup loidy, an abnormal balance of chromosomes. Because symmetrical segrega tion of chromosomes depends on exactly two copies of mitosis genes, an euploidy involving chromosomes with mitosis genes will destabilize the karyotype. The hypothesis predicts that the degree of genetic instabi lity should be proportional to the degree of aneuploidy. Thus it shoul d be difficult, if not impossible, to maintain the particular karyotyp e of a highly aneuploid cancer cell on clonal propagation. This predic tion was confirmed with clonal cultures of chemically transformed, ane uploid Chinese hamster embryo cells. It was found that the higher the ploidy factor of a clone, the more unstable was its karyotype. The plo idy factor is the quotient of the modal chromosome number divided by t he normal number of the species. Transformed Chinese hamster embryo ce lls with a ploidy factor of 1.7 were estimated to change their karyoty pe at a rate of about 3% per generation, compared with 1.8% for cells with a ploidy factor of 0.95. Because the background noise of karyotyp ing is relatively high, the cells with low ploidy factor may be more s table than our method suggests. The karyotype instability of human col on cancer cell lines, recently analyzed by Lengnauer Et al. [Lengnauer , C., Kinder, K. W. & Vogelstein, B. (1997) Nature (London) 386, 623-6 37], also corresponds exactly to their degree of aneuploidy. We conclu de that aneuploidy is sufficient to explain genetic instability and th e resulting karyotypic and phenotypic heterogeneity of cancer cells, i ndependent of gene mutation. Because aneuploidy has also been proposed to cause cancer, our hypothesis offers a common, unique mechanism of altering and simultaneously destabilizing normal cellular phenotypes.