Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy

Abstract

For nearly a century, cancer has been blamed on somatic mutation. But it is still unclear whether this mutation is aneuploidy, an abnormal balance of chromosomes, or gene mutation. Despite enormous efforts, the currently popular gene mutation hypothesis has failed to identify cancer-specific mutations with transforming function and cannot explain why cancer occurs only many months to decades after mutation by carcinogens and why solid cancers are aneuploid, although conventional mutation does not depend on karyotype alteration. A recent high-profile publication now claims to have solved these discrepancies with a set of three synthetic mutant genes that "suffices to convert normal human cells into tumorigenic cells." However, we show here that even this study failed to explain why it took more than "60 population doublings" from the introduction of the first of these genes, a derivative of the tumor antigen of simian virus 40 tumor virus, to generate tumor cells, why the tumor cells were clonal although gene transfer was polyclonal, and above all, why the tumor cells were aneuploid. If aneuploidy is assumed to be the somatic mutation that causes cancer, all these results can be explained. The aneuploidy hypothesis predicts the long latent periods and the clonality on the basis of the following two-stage mechanism: stage one, a carcinogen (or mutant gene) generates aneuploidy; stage two, aneuploidy destabilizes the karyotype and thus initiates an autocatalytic karyotype evolution generating preneoplastic and eventually neoplastic karyotypes. Because the odds are very low that an abnormal karyotype will surpass the viability of a normal diploid cell, the evolution of a neoplastic cell species is slow and thus clonal, which is comparable to conventional evolution of new species.

Figure 1

The chromosomes of a representative aneuploid cell of the tumorigenic human HA1 ER (a) and BJ ELR (b) cell lines. Metaphase chromosomes of these cells were prepared as described previously (51) and photographed ×630 after Giemsa staining. The HA1 ER metaphase shown contains 78 and the BJ ELR metaphase contains 82 chromosomes.

Figure 2

A two-stage model for how carcinogens may cause cancer via aneuploidy. Stage one: a carcinogen “initiates” carcinogenesis by generating an aneuploid cell. Stage two: aneuploidy destabilizes symmetric chromosome segregation, because it unbalances spindle and chromosomal proteins and centrosome numbers by unbalancing their chromosomal templates (see text). As a result, aneuploidy initiates autocatalytic karyotype variation and evolution, which generates new lethal, preneoplastic and eventually neoplastic karyotypes. The autocatalytic karyotype evolution would explain the previously unresolved carcinogen-independent transformation of an “initiated” preneoplastic into a neoplastic cell (8, 9, 62). The notorious long latent periods from initiation to carcinogenesis would be a consequence of the low probability of generating by chance a karyotype that can outperform normal cells. Autocatalytic karyotype variation would also explain the notorious genetic instability and phenotypic heterogeneity of cancer cells (9, 43).