Genetic instability of cancer cells is proportional to their degree of aneuploidy

Abstract

Genetic and phenotypic instability are hallmarks of cancer cells, but their cause is not clear. The leading hypothesis suggests that a poorly 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 aneuploidy, an abnormal balance of chromosomes. Because symmetrical segregation of chromosomes depends on exactly two copies of mitosis genes, aneuploidy involving chromosomes with mitosis genes will destabilize the karyotype. The hypothesis predicts that the degree of genetic instability should be proportional to the degree of aneuploidy. Thus it should be difficult, if not impossible, to maintain the particular karyotype of a highly aneuploid cancer cell on clonal propagation. This prediction was confirmed with clonal cultures of chemically transformed, aneuploid Chinese hamster embryo cells. It was found that the higher the ploidy factor of a clone, the more unstable was its karyotype. The ploidy factor is the quotient of the modal chromosome number divided by the normal number of the species. Transformed Chinese hamster embryo cells with a ploidy factor of 1.7 were estimated to change their karyotype 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 karyotyping is relatively high, the cells with low ploidy factor may be more stable than our method suggests. The karyotype instability of human colon cancer cell We conclude that aneuploidy is sufficient to explain genetic instability and the resulting karyotypic and phenotypic heterogeneity of cancer cells, independent 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.

Progressive methylation during the serrated neoplasia pathway of the colorectum

“…However, the serrated adenomas exclusively showed near-diploid DNA indices rather than the high aneuploid indices reported in traditional tubular or villous adenomas. Genetic instability of tumors is proportional to their degree of aneuploidy, 29,30 so the near-diploid DNA indices observed in our four aneuploid serrated adenomas and carcinomas suggest that subtle chromosomal changes may underlie the serrated neoplasia pathway. Aneuploidy observed in serrated adenomas with both lowgrade atypism and carcinomas also suggests that aneuploidization occurs early during tumor progression.…”

An alternative, non-intrauterine hypothesis, based on maternal mitochondrial oocyte inheritance, to explain inconsistent findings of birth weight on (breast) cancer risk

“…In the surviving foetuses carrying aneuploidy and/or a higher propensity to aneuploidy, a high maternal age is reflected in an increased risk of several cancers in their offspring (Abelin, 1965). From this perspective of defective growth and development, it is interesting that aneuploidy is also an essential trait of cancer cells, as described already more than hundred years ago by Boveri (Deusberg, 1998). Also in adult cells and tissues, mitochondria play a pivoting role in proper cell function.…”

“…Also in adult cells and tissues, mitochondria play a pivoting role in proper cell function. Improper functioning cells can be eliminated selectively by apoptosis in which mitochondria also play a cruxial role (Hengartner, 2000) or when escaping apoptosis, show signs of aneuploidy and become cancerous (Deusberg, 1998).…”

Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor

“…Dicha teoría ha sido corroborada en numerosos estudios citogenéticos de tumores sólidos. Los recientes trabajos de Duesberg et al (28,29) reevalúan los postulados de Boveri, utilizando modelos in vitro con células transformadas, en los que se ratifica que el cáncer se origina por aneuploidías (pérdida o ganancia de cromosomas) y que la inestabilidad cromosómica es proporcional al grado de la aneuploidía y al número de cromosomas afectados (6,29). En conclusión, Duesberg confirma que las alteraciones cromosómicas juegan un papel fundamental en la iniciación y progresión del cáncer, y que, además, los cromosomas de las células cancerosas son inestables por causa de la aneuploidía.…”

“…Numerosos estudios informan la presencia de aneuploidías en casi todos los tumores sólidos humanos que se han analizado (2,4). Los recientes trabajos realizados por Duesberg et al (5) están dirigidos a corroborar la anterior teoría y en ellos se establece que la inestabilidad cromosómica de las células tumorales es proporcional al grado de la aneuploidía o del desequilibrio cromosómico (6). Por esta vía, las alteraciones cromosómicas afectan la expresión de genes clave, como son los del control del ciclo celular, de la estabilidad genómica, de la angiogénesis, de la apoptosis y de la reparación, entre muchos otros (4).…”