The many complex phenotypes of
cancer have all been attributed to "somatic mutation." These phenotypes include
anaplasia, autonomous growth,
metastasis, abnormal cell morphology,
DNA indices ranging from 0.5 to over 2, clonal origin but unstable and non-clonal karyotypes and phenotypes, abnormal centrosome numbers, immortality in vitro and in
transplantation, spontaneous progression of
malignancy, as well as the exceedingly slow kinetics from
carcinogen to
carcinogenesis of many months to decades. 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 it 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, (1) many
carcinogens do not mutate genes, (2) there is no functional proof that mutant genes cause
cancer, and (3) 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, either by fragmenting chromosomes or by damaging the spindle apparatus. In stage two, ever new and eventually tumorigenic karyotypes evolve autocatalytically because
aneuploidy destabilizes the karyotype, ie. causes 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 is analogous to speciation. The slow kinetics of
carcinogenesis reflects the low probability of generating by random chromosome reassortments a karyotype that surpasses the viability of a normal cell, similar again to natural speciation. There is correlative and functional proof of principle: (1) solid
cancers are
aneuploid; (2) genotoxic and non-genotoxic
carcinogens cause
aneuploidy; (3) the biochemical phenotypes of cells are severely altered by
aneuploidy affecting the dosage of thousands of genes, but are virtually un-altered by mutations of known hypothetical oncogenes and tumor suppressor genes; (4)
aneuploidy immortalizes cells; (5) non-cancerous
aneuploidy generates abnormal phenotypes in all species tested, e.g.,
Down syndrome; (6) the degrees of
aneuploidies are proportional to the degrees of abnormalities in non-cancerous and cancerous cells; (7)
polyploidy also varies
biological phenotypes; (8) variation of the numbers of chromosomes is the basis of speciation. Thus,
aneuploidy falls within the definition of speciation, and
cancer is a species of its own. The
aneuploidy hypothesis offers new prospects of
cancer prevention and
therapy.