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Keywords = near-triploid cancer

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16 pages, 4511 KiB  
Article
Meta-Analysis of Cancer Triploidy: Rearrangements of Genome Complements in Male Human Tumors Are Characterized by XXY Karyotypes
by Ninel M. Vainshelbaum, Pawel Zayakin, Regina Kleina, Alessandro Giuliani and Jekaterina Erenpreisa
Genes 2019, 10(8), 613; https://doi.org/10.3390/genes10080613 - 13 Aug 2019
Cited by 11 | Viewed by 5017
Abstract
Triploidy in cancer is associated with poor prognosis, but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy. In silico meta-analysis was performed on 15 male malignant and five benign tumor cohorts (2928 karyotypes) [...] Read more.
Triploidy in cancer is associated with poor prognosis, but its origins remain unclear. Here, we attempted to differentiate between random chromosomal and whole-genome origins of cancer triploidy. In silico meta-analysis was performed on 15 male malignant and five benign tumor cohorts (2928 karyotypes) extracted from the Mitelman Database, comparing their ploidy and combinations of sex chromosomes. A distinct near-triploid fraction was observed in all malignant tumor types, and was especially high in seminoma. For all tumor types, X-chromosome doubling, predominantly observed as XXY, correlated strongly with the near-triploid state (r ≈ 0.9, p < 0.001), negatively correlated with near-diploidy, and did not correlate with near-tetraploidy. A smaller near-triploid component with a doubled X-chromosome was also present in three of the five benign tumor types, especially notable in colon adenoma. Principal component analysis revealed a non-random correlation structure shaping the X-chromosome disomy distribution across all tumor types. We suggest that doubling of the maternal genome followed by pedogamic fusion with a paternal genome (a possible mimic of the fertilization aberration, 69, XXY digyny) associated with meiotic reprogramming may be responsible for the observed rearrangements of genome complements leading to cancer triploidy. The relatively frequent loss of the Y-chromosome results as a secondary factor from chromosome instability. Full article
(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)
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20 pages, 2713 KiB  
Concept Paper
When Three Isn’t a Crowd: A Digyny Concept for Treatment-Resistant, Near-Triploid Human Cancers
by Kristine Salmina, Bogdan I. Gerashchenko, Michael Hausmann, Ninel M. Vainshelbaum, Pawel Zayakin, Juris Erenpreiss, Talivaldis Freivalds, Mark S. Cragg and Jekaterina Erenpreisa
Genes 2019, 10(7), 551; https://doi.org/10.3390/genes10070551 - 19 Jul 2019
Cited by 14 | Viewed by 6134
Abstract
Near-triploid human tumors are frequently resistant to radio/chemotherapy through mechanisms that are unclear. We recently reported a tight association of male tumor triploidy with XXY karyotypes based on a meta-analysis of 15 tumor cohorts extracted from the Mitelman database. Here we provide a [...] Read more.
Near-triploid human tumors are frequently resistant to radio/chemotherapy through mechanisms that are unclear. We recently reported a tight association of male tumor triploidy with XXY karyotypes based on a meta-analysis of 15 tumor cohorts extracted from the Mitelman database. Here we provide a conceptual framework of the digyny-like origin of this karyotype based on the germline features of malignant tumors and adaptive capacity of digyny, which supports survival in adverse conditions. Studying how the recombinatorial reproduction via diploidy can be executed in primary cancer samples and HeLa cells after DNA damage, we report the first evidence that diploid and triploid cell sub-populations constitutively coexist and inter-change genomes via endoreduplicated polyploid cells generated through genotoxic challenge. We show that irradiated triploid HeLa cells can enter tripolar mitosis producing three diploid sub-subnuclei by segregation and pairwise fusions of whole genomes. Considering the upregulation of meiotic genes in tumors, we propose that the reconstructed diploid sub-cells can initiate pseudo-meiosis producing two “gametes” (diploid “maternal” and haploid “paternal”) followed by digynic-like reconstitution of a triploid stemline that returns to mitotic cycling. This process ensures tumor survival and growth by (1) DNA repair and genetic variation, (2) protection against recessive lethal mutations using the third genome. Full article
(This article belongs to the Special Issue Chromosomal Heterogeneity and Human Diseases)
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