title: Karyotypic evolutions of cancer species in rats during the long latent periods after injection of nitrosourea.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  Here 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Molecular and Cell Biology, Donner Laboratory, University of California at Berkeley, Berkeley, CA USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Bloomfield
authors.affiliation: Department of Molecular and Cell Biology, Donner Laboratory, University of California at Berkeley, Berkeley, CA USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: McCormack
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Mandrioli
authors.affiliation: Gynmed Ambulatorium, Mariahilferguertel 37, 1150 Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Fiala
authors.affiliation: Department of Molecular Carcinogenesis, M. D. Anderson Cancer Center, Smithville, Texas 78957 USA.
authors.forename: C Marcelo
authors.initials: CM
authors.lastname: Aldaz
authors.affiliation: Department of Molecular and Cell Biology, Donner Laboratory, University of California at Berkeley, Berkeley, CA USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Duesberg
keywords: Carcinogens function as aneuploidogens; Individual clonal karyotypes of cancers; Karyotype arrays; Persistent non-clonal hyperplasias; Single-step origins of cancer karyotypes