Origin of metastases: Subspecies of cancers generated by intrinsic karyotypic variations

Duesberg, Peter H.; Iacobuzio‐Donahue, Christine A.; Brosnan, Jacqueline A.; McCormack, Amanda; Mandrioli, Daniele; Chen, Lewis

doi:10.4161/cc.11.6.19580

Cited by 19 publications

(36 citation statements)

References 70 publications

(114 reference statements)

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“…Therefore, we test here the theory that metastasis is a form of speciation, which predicts individual metastasis-specific karyotypes and phenotypes, rather than common mutations. This theory extends and confirms preliminary karyotypic evidence for metastasis from two labs including ours [43, 75, 88]. …”

Section: Introductionsupporting

confidence: 90%

“…In searching for these elusive metastasis-genes, it was also 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, 75–77] we have asked here, whether the proclivity of cancers to metastasize might be determined by cancer-specific aneuploidy.…”

Section: Introductionmentioning

confidence: 99%

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Inherent variability of cancer-specific aneuploidy generates metastases

Bloomfield

Duesberg

2016

Mol Cytogenet

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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.”

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Section: Introductionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Inherent variability of cancer-specific aneuploidy generates metastases

Bloomfield

Duesberg

2016

Mol Cytogenet

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“…Consistent evolution of karyotypes and phenotypes in different models was shown Duesberg et al, 2007Duesberg et al, , 2011Duesberg et al, , 2012Klein et al, 2010;Li et al, 2009;McCormack et al, 2013;Nicholson and Duesberg, 2009). The reason is that chromosome changes alter system inheritance (the order of genes along the chromosomes and within the genome) and lead to the diverse and wide-spread changes in gene expression at both transcriptional and translational levels.…”

Section: Both Stable Plasmid Dna Transfection and Overexpression Of Cmentioning

confidence: 83%

“…The aberrant karyotype, genomic heterogeneity, and constitutive expression of adenoviral E1 gene make transcriptome of 293 cells severely deregulated, bringing to naught affords to elucidate an authentic cell type of origin and present phenotype. It should be noted that all immortalized cell lines irrespectively of an "immortalizing agent" (viral genomes/ oncogenes, telomerase reverse transcriptase catalytic subunit (TERT), transcription factors, chemical treatment or spontaneously) are characterized by abnormal karyotypes, and genome alterations are essential for cellular immortalization, transformation, metastasis and drug resistance (Duesberg et al, 2011(Duesberg et al, , 2012Duesberg and McCormack, 2013;Heng et al, 2010Heng et al, , 2011Heng et al, , 2013Kavsan, 2012, 2013). The different types of stress (such as over-or under-expression of oncogenes or tumor suppressor genes, drug treatment, medium growth changes, and other experimental manipulations) can trigger/promote genome instability and the generation of population diversity through the combination of clonal and non-clonal chromosomal aberrations, epigenetic and nongenetic heterogeneity.…”

Section: Discussionmentioning

confidence: 98%

HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution

Stepanenko

Dmitrenko

2015

Gene

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200

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“…The MitelmanNational Cancer Institute database currently catalogs Ͼ63 000 human cancers with individual clonal karyotypes distinct from their cells of origin, including Ͼ2000 gene fusions (23 ). This massive collection of individual clonal karyotypes is derived from individual progressive mutational events provided by single-nucleotide polymorphisms and chromosomal CNVs in a cellular form of Darwinian speciation (24,25 ). Tumor structural chromosomal variations observed as regional DNA ploidy heterogeneity are recapitulated in the cfDNA as a function of apoptosis and the cellular release of nucleosomes that can be distinguished from typical cellular apoptotic DNA.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Instability in Cell-Free DNA Is a Serum Biomarker for Prostate Cancer

Schütz¹,

Akbari

Beck³

et al. 2015

Clinical Chemistry

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BACKGROUND Genomic instability resulting in copy number variation is a hallmark of malignant transformation and may be identified through massive parallel sequencing. Tumor-specific cell free DNA (cfDNA) present in serum and plasma provides a real-time, easily accessible surrogate. METHODS DNA was extracted from serum of 204 patients with prostate cancer (Gleason score 2–10), 207 male controls, and patients with benign hyperplasia (n = 10) and prostatitis (n = 10). DNA was amplified by use of random primers, tagged with molecular identifiers, sequenced on a SOLID system, and aligned to the human genome. We evaluated the number of sequence reads of cfDNA in sliding 100-kbp intervals for variation from controls. We used chromosomal regions with significant variations in alignment hits for their ability to segregate patients and matched controls. RESULTS Using ROC curves to assess diagnostic performance, we evaluated the number of regions in a first subset (n = 177), with variations in alignment hits alone, provided an area under the curve (AUC) of 0.81 (95% CI 0.7–0.9, P < 0.001). Using 5 rounds of 10-fold cross-validation with the full data set, we established a final model that discriminated prostate cancer from controls with an AUC of 0.92 (0.87–0.95), reaching a diagnostic accuracy of 83%. Both benign prostatic hypertrophy and prostatitis could be distinguished from prostate cancer by use of cfDNA, with an accuracy of 90%. CONCLUSIONS Assessment of a limited number of chromosomal structural instabilities by use of massive parallel sequencing of cfDNA was sufficient to distinguish between prostate cancer and controls. This large cohort demonstrates the utility of cfDNA in prostate cancer recently established in other malignant neoplasms.

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Origin of metastases: Subspecies of cancers generated by intrinsic karyotypic variations

Cited by 19 publications

References 70 publications

Inherent variability of cancer-specific aneuploidy generates metastases

Inherent variability of cancer-specific aneuploidy generates metastases

HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution

Chromosomal Instability in Cell-Free DNA Is a Serum Biomarker for Prostate Cancer

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