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When three isn't a crowd: a digyny concept for treatment-resistant, near-triploid human cancers

When three isn't a crowd: a digyny concept for treatment-resistant, near-triploid human cancers
When three isn't a crowd: a digyny concept for treatment-resistant, near-triploid human cancers
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.
2073-4425
1-13
Salmina, Kristine
00a98b4d-8de8-4e78-99f7-a8834851d209
Gerashchenko, Bogdan I.
f11f8973-3137-4cae-809d-30817c9656bf
Hausmann, Michael
074d1ba1-cff7-4976-8302-f9b6b7183032
Vainshelbaum, Ninel M.
069ba573-1a06-49be-8f06-06e2446a6a4a
Zayakin, Pawel
46c4c4ba-8c2c-4569-bf09-206d26469b2c
Erenpreiss, Juris
9913872f-bb2e-459b-b597-52d4fda6c1ed
Freivalds, Talivaldis
2381b649-f48a-4a2e-b1b9-548889a34dbf
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Erenpreisa, Jekaterina
70b5fecb-7208-431f-bd35-ec498edc0033
Salmina, Kristine
00a98b4d-8de8-4e78-99f7-a8834851d209
Gerashchenko, Bogdan I.
f11f8973-3137-4cae-809d-30817c9656bf
Hausmann, Michael
074d1ba1-cff7-4976-8302-f9b6b7183032
Vainshelbaum, Ninel M.
069ba573-1a06-49be-8f06-06e2446a6a4a
Zayakin, Pawel
46c4c4ba-8c2c-4569-bf09-206d26469b2c
Erenpreiss, Juris
9913872f-bb2e-459b-b597-52d4fda6c1ed
Freivalds, Talivaldis
2381b649-f48a-4a2e-b1b9-548889a34dbf
Cragg, Mark S.
ec97f80e-f3c8-49b7-a960-20dff648b78c
Erenpreisa, Jekaterina
70b5fecb-7208-431f-bd35-ec498edc0033

Salmina, Kristine, Gerashchenko, Bogdan I., Hausmann, Michael, Vainshelbaum, Ninel M., Zayakin, Pawel, Erenpreiss, Juris, Freivalds, Talivaldis, Cragg, Mark S. and Erenpreisa, Jekaterina (2019) When three isn't a crowd: a digyny concept for treatment-resistant, near-triploid human cancers. Genes, 10 (7), 1-13, [551]. (doi:10.3390/genes10070551).

Record type: Article

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 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.

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Accepted/In Press date: 19 June 2019
e-pub ahead of print date: 19 July 2019
Published date: 19 July 2019

Identifiers

Local EPrints ID: 432760
URI: http://eprints.soton.ac.uk/id/eprint/432760
ISSN: 2073-4425
PURE UUID: 9e32a336-8f73-420d-961d-b64c829cf9a9
ORCID for Mark S. Cragg: ORCID iD orcid.org/0000-0003-2077-089X

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Date deposited: 26 Jul 2019 16:30
Last modified: 26 Nov 2021 02:40

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Contributors

Author: Kristine Salmina
Author: Bogdan I. Gerashchenko
Author: Michael Hausmann
Author: Ninel M. Vainshelbaum
Author: Pawel Zayakin
Author: Juris Erenpreiss
Author: Talivaldis Freivalds
Author: Mark S. Cragg ORCID iD
Author: Jekaterina Erenpreisa

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