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
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
(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.