Abstract
BackgroundA century of research has established that cancers arise from tissues exposed to carcinogens only after long latencies of years to decades and have individual clonal karyotypes. Since speciation from known precursors also depends on long latencies and new species also have individual karyotypes, we and others have recently proposed that carcinogenesis is a form of speciation. According to this theory karyotypic evolutions generate new cancer species from normal cells as follows: Carcinogens induce aneuploidy (Figure 1). By unbalancing thousands of genes aneuploidy automatically destabilizes the karyotype and thus catalyzes random karyotypic variations. Selections of variants with proliferative phenotypes form non-clonal hyperplasias with persistently varying karyotypes. Very rare karyotypic variations form new cancer species with individual clonal karyotypes. Despite destabilization by the resulting congenital aneuploidies, cancer karyotypes are stabilized within narrow margins of variation by clonal selections for cancer-specific autonomy. Because all non-cancerous aneuploidies are unstable, all aneusomies of prospective cancers are joined in single-steps, rather than gradually. Since this mechanism is very inefficient, it predicts long latent periods from carcinogens to cancers and individual clonal cancer karyotypes.ResultsHere we have tested the predicted roles of karyotypic evolutions during the time course of carcinogenesis in an established experimental system. In this system injection of nitrosourea induces in female rats non-invasive mammary hyperplasias (“tumors”) after two or more months, and invasive carcinomas after six or more months. Accordingly four specific predictions were tested: (1) Invasive cancers are late and carry individual clonal karyotypes and phenotypes, (2) Persistent hyperplasias carry non-clonal karyotypes, (3) Non-clonal hyperplasias generate clonal cancers spontaneously but rarely, (4) Cancer-karyotypes arise with all individual clonal aneusomies in single-steps. All four predictions were experimentally confirmed.ConclusionsOur results along with the literature reveal a coherent karyotypic mechanism of carcinogenesis: Carcinogens induce aneuploidy. The inherent instability of aneuploidy automatically catalyzes new karyotypic variations. Aneuploid karyotypes with proliferative phenotypes form varying non-clonal hyperplasias. Rare variations form cancer species with individual clonal karyotypes, which are stabilized by clonal selection for autonomy. The low odds of this mechanism explain the long latencies of carcinogenesis, the individuality and karyotypic clonality of cancers.
Highlights
A century of research has established that cancers arise from tissues exposed to carcinogens only after long latencies of years to decades and have individual clonal karyotypes
In addition we adduce evidence that cancer karyotypes arise with all prospective clonal cancer-specific aneusomies in single-steps, rather than gradually, because non-cancerous aneuploid intermediates are too unstable to support gradual accumulations
Test-1: are carcinomas late and carry individual clonal karyotypes and phenotypes? The speciation theory attributes the long latencies from carcinogen to carcinogenesis and the clonal individuality of cancers to very rare, and typically late karyotypic variations, which generate new autonomous cancer-species with individual clonal karyotypes
Summary
A century of research has established that cancers arise from tissues exposed to carcinogens only after long latencies of years to decades and have individual clonal karyotypes. The mutation theory explains the long latencies of years to decades from atomic bomb explosions in 1945 [5,9] or from X-ray therapies of tuberculosis [6] to subsequent cancers by requirements of subsequent mutations. This seems odd, in view of the huge loads of mutagenic radiations long before carcinogenesis. Brash and Cairns stated in 2009, “mutagenic carcinogens cause just one or two events and that these are followed by steps that accumulate solely with the passage of time” [32]
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