Karyotype alteration generates the neoplastic phenotypes of SV40-infected human and rodent cells

Abstract

BackgroundDespite over 50 years of research, it remains unclear how the DNA tumor viruses SV40 and Polyoma cause cancers. Prevailing theories hold that virus-coded Tumor (T)-antigens cause cancer by inactivating cellular tumor suppressor genes. But these theories don’t explain four characteristics of viral carcinogenesis: (1) less than one in 10,000 infected cells become cancer cells, (2) cancers have complex individual phenotypes and transcriptomes, (3) recurrent tumors without viral DNA and proteins, (4) preneoplastic aneuploidies and immortal neoplastic clones with individual karyotypes.ResultsAs an alternative theory we propose that viral carcinogenesis is a form of speciation, initiated by virus-induced aneuploidy. Since aneuploidy destabilizes the karyotype by unbalancing thousands of genes it catalyzes chain reactions of karyotypic and transcriptomic evolutions. Eventually rare karyotypes evolve that encode cancer-specific autonomy of growth. The low probability of forming new autonomous cancer-species by random karyotypic and transcriptomic variations predicts individual and clonal cancers. Although cancer karyotypes are congenitally aneuploid and thus variable, they are stabilized or immortalized by selections for variants with cancer-specific autonomy. Owing to these inherent variations cancer karyotypes are heterogeneous within clonal margins. To test this theory we analyzed karyotypes and phenotypes of SV40-infected human, rat and mouse cells developing into neoplastic clones. In all three systems we found (1) preneoplastic aneuploidies, (2) neoplastic clones with individual clonal but flexible karyotypes and phenotypes, which arose from less than one in 10,000 infected cells, survived over 200 generations, but were either T-antigen positive or negative, (3) spontaneous and drug-induced variations of neoplastic phenotypes correlating 1-to-1 with karyotypic variations.ConclusionsSince all 14 virus-induced neoplastic clones tested contained individual clonal karyotypes and phenotypes, we conclude that these karyotypes have generated and since maintained these neoplastic clones. Thus SV40 causes cancer indirectly, like carcinogens, by inducing aneuploidy from which new cancer-specific karyotypes evolve automatically at low rates. This theory explains the (1) low probability of carcinogenesis per virus-infected cell, (2) the individuality and clonal flexibility of cancer karyotypes, (3) recurrence of neoplasias without viral T-antigens, and (4) the individual clonal karyotypes, transcriptomes and immortality of virus-induced neoplasias - all unexplained by current viral theories.

Inherent variability of cancer-specific aneuploidy generates metastases

“…This absence of precursors of metastases confirms previous results from others including us [43, 76, 77, 126, 127]. In addition our results confirm the predicted absence of precursors of the many non-metastatic variants with multiple aneusomies and with the same complexities as their metastatic counterparts (Figs.…”

“…This technique is able to detect karyotypic clonality, even if a minority of the chromosomes of a given karyotype is non-clonal [76, 108, 109] (Background). The technique arrays the copy numbers of individual chromosomes of 20 cancer karyotypes in 3-dimensional tables.…”

“…But ploidy variation in cancer cells is typically not exactly even, and is another independent characteristic of cancer cells that may increase or decrease oncogenicity by changing the dosage of genes evenly and non-evenly [76, 77, 112–114]. Its occurrence also seems to be proportional to the degree of cancer-specific aneuploidy [76, 115]. Balanced ploidy changes also occur in the development of some normal animal [116] and plant cells [117] and thus enhance the general output of cells.…”

“…This proposal is based on the absence of the many intermediates or precursors predicted by the linear model, which are probably absent, because they are not viable [43, 76, 77, 125–127] and the finding of others that all aneusomies of the cancers analyzed carried genetic markers only from one, instead of both sets of normal parental chromosomes of an organism [128, 129]. …”

Is DNA methylation the new guardian of the genome?

“…Duesberg et al [47] have proposed that carcinogenesis, such as that caused by SV40 virus, is due to induced aneuploidy, which destabilizes the karyotype which progressively evolves to autonomous clonal cancers.…”