The complex phenotypes of cancer, such as anaplasia, autonomous growth, metastasis, abnormal cell morphology, DNA indices ranging from 0,5 to over 2, unstable and non-clonal karyotypes and phenotypes despite its clonal origin, abnormal centrosome numbers, as well as the exceedingly slow kinetics from carcinogen to carcinogenesis of many months to decades have all been attributed to "somatic mutation". However, it has yet to be determined whether this mutation is aneuploidy, an abnormal number of chromosomes, or gene mutation.
A century ago Boveri proposed cancer is caused by aneuploidy, because aneuploidy correlates with cancer and because it generates "pathological" phenotypes in sea urchins. But half a century later, when cancers were found to be non-clonal for aneuploidy, but clonal for somatic gene mutations, this hypothesis was abandoned. As a result aneuploidy is now generally viewed as a consequence, and mutated genes as a cause of cancer although, (i) many carcinogens are not genotoxic, (ii) there is no functional proof that mutant genes cause cancer, and (iii) mutation is fast but carcinogenesis is exceedingly slow .
Intrigued by the enormous mutagenic potential of aneuploidy, we undertook biochemical and biological analyses of aneuploidy and gene mutation which show that aneuploidy is probably the only mutation that can explain all aspects of carcinogenesis . On this basis we can now offer a coherent two-stage mechanism of carcinogenesis. In stage one, carcinogens cause aneuploidy which destabilizes the karyotype, and in stage two, aneuploidy evolves autocatalytically generating ever new and eventually tumorigenic karyotypes, ie. "genetic instability" . Thus cancer cells derive their unique and complex phenotypes from random chromosome number mutation, a process that is similar to regrouping assembly lines of a car factory and also to speciation. The slow kinetics of carcinogenesis reflect the low probability of generating by random chromosome reassortments a karyotype that surpasses the viability of a normal cell, similar again to natural speciation.
The hypothesis makes several, testable predictions:
(i) Carcinogens function as aneuploidogens. This could be tested by measuring the effect of carcinogens, such as polycyclic aromatic hydrocarbons, X-rays, and alkylating agents on the spindle apparatus, and on the karyotype of treated animal or human cells.
(ii) Aneuploidy by unbalancing the doses of normal spindle proteins. This could be tested by transfecting diploid cells with spindle genes such as tubulin.
(iii) Genetic instability of cancer cells. The aneuploidy hypothesis suggests that drug-resistance, the notorious obstacle of cancer chemotherapy, may be due to chromosome number mutation, rather than to conventional gene mutation . This could be tested by comparing the rates of drug-resistant variants among aneuploid cancer cells to those of their diploid normal counterparts.
(iv) Long latent period from carcinogen to cancer. This could be studied by determining the kinetics from the introduction of aneuploidy by carcinogens until morphological transformation in vitro or tumorigenicity in animals. According to this hypothesis tumor promoters, defined as non-genotoxic substances that accelerate tumorigenesis , would enhance aneuploidization and thus shorten the latent period.
The aneuploidy hypothesis offers new prospects of cancer prevention based on detecting aneuploidogenic substances and aneuploid preneoplastic lesions.