Inherent variability of cancer-specific aneuploidygenerates metastases.

Peter Duesberg,Mathew Bloomfield

doi:10.1186/s13039-016-0297-x

Abstract

BackgroundThe genetic basis of metastasis is still unclear because metastases carry individual karyotypes and phenotypes, rather than consistent mutations, and are rare compared to conventional mutation. There is however correlative evidence that metastasis depends on cancer-specific aneuploidy, and that metastases are karyotypically related to parental cancers. Accordingly we propose that metastasis is a speciation event. This theory holds that cancer-specific aneuploidy varies the clonal karyotypes of cancers automatically by unbalancing thousands of genes, and that rare variants form new autonomous subspecies with metastatic or other non-parental phenotypes like drug-resistance – similar to conventional subspeciation.ResultsTo test this theory, we analyzed the karyotypic and morphological relationships between seven cancers and corresponding metastases. We found (1) that the cellular phenotypes of metastases were closely related to those of parental cancers, (2) that metastases shared 29 to 96% of their clonal karyotypic elements or aneusomies with the clonal karyotypes of parental cancers and (3) that, unexpectedly, the karyotypic complexity of metastases was very similar to that of the parental cancer. This suggests that metastases derive cancer-specific autonomy by conserving the overall complexity of the parental karyotype. We deduced from these results that cancers cause metastases by karyotypic variations and selection for rare metastatic subspecies. Further we asked whether metastases with multiple metastasis-specific aneusomies are assembled in one or multiple, sequential steps. Since (1) no stable karyotypic intermediates of metastases were observed in cancers here and previously by others, and (2) the karyotypic complexities of cancers are conserved in metastases, we concluded that metastases are generated from cancers in one step – like subspecies in conventional speciation.ConclusionsWe conclude that the risk of cancers to metastasize is proportional to the degree of cancer-specific aneuploidy, because aneuploidy catalyzes the generation of subspecies, including metastases, at aneuploidy-dependent rates. Since speciation by random chromosomal rearrangements and selection is unpredictable, the theory that metastases are karyotypic subspecies of cancers also explains Foulds’ rules, which hold that the origins of metastases are “abrupt” and that their phenotypes are “unpredictable.”

Highlights

The genetic basis of metastasis is still unclear because metastases carry individual karyotypes and phenotypes, rather than consistent mutations, and are rare compared to conventional mutation
No evidence for consistent metastasis-specific mutations In 1954 Foulds showed that cancers progress to metastases stochastically or “abruptly” and with diverse “unpredictable” phenotypes and concluded that “it is inadvisable to attribute to mutation” the great diversity of the individual phenotypes of metastases [5]
The Biology of Cancer states in 2014–60 years after Foulds first questioned mutations - that “it is clear that the identities of many of the genes that are involved in programming metastasis have been elusive.” [3]

Summary

Introduction

The genetic basis of metastasis is still unclear because metastases carry individual karyotypes and phenotypes, rather than consistent mutations, and are rare compared to conventional mutation. We propose that metastasis is a speciation event This theory holds that cancer-specific aneuploidy varies the clonal karyotypes of cancers automatically by unbalancing thousands of genes, and that rare variants form new autonomous subspecies with metastatic or other non-parental phenotypes like drug-resistance – similar to conventional subspeciation. The Biology of Cancer states in 2014–60 years after Foulds first questioned mutations - that “it is clear that the identities of many of the genes that are involved in programming metastasis have been elusive.” [3] In searching for these elusive metastasisgenes, it was observed that the proclivity of cancers to metastasize is determined prior to metastasis, is “preordained” [69] or “predetermined” [74]. Considering the elusive search for metastasis-genes and our prior work on the karyotypic basis of cancer and metastasis [43, 75,76,77] we have asked here, whether the proclivity of cancers to metastasize might be determined by cancer-specific aneuploidy

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Results

Conclusion