When Three Isn't a Crowd: A Digyny Concept for Treatment-Resistant, Near-Triploid Human Cancers.

Salmina Salmina,Erenpreiss Erenpreiss,Gerashchenko Gerashchenko,Zayakin Zayakin,Erenpreisa Erenpreisa,Freivalds Freivalds,Cragg Cragg,Vainshelbaum Vainshelbaum,Hausmann Hausmann

doi:10.3390/genes10070551

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.

Highlights

After assuming that a digyny-like process can convert diploid tumor cells into triploidy “digynic parthenotes”, we suggest as a working hypothesis, that on its side, the near-triploid tumor cell line uses the endoreduplication platform to create the diploid stemline, capable of undergoing the recombinatorial pseudo-meiosis and reciprocal exchange with “digyny”
We report below some data relevant to this hypothesis from our studies of male tumors from the Mitelman database and from chemoresistance study of breast cancer tumors in patients
We found here that near-triploid HeLa cells begin to increasingly produce the diploid and tetraploid subfractions after irradiation, likely by a-cytokinetic tripolar mitosis of near-triploid cells endoreduplicated to 6n and 12n and that their proportion increased from ~ 6% on day two to ~40–50%

Summary

Introduction

Organismal triploidy in humans is known to be lethal and causes early spontaneous abortions [2].In contrast, aneuploidy is a well-tolerated characteristic hallmark of most human tumors [3,4,5].many established tumor cell lines used as models for cancer research or pharmacological studies exhibit near-triploidy [6] and many chemotherapy-resistant cancers display it in vivo [7,8,9].In the accompanying article [10] we recently presented data for the origin of tumor triploidy based on the in silico meta-analysis of 2928 karyotypes from 15 malignant solid tumor types of male patientsGenes 2019, 10, 551; doi:10.3390/genes10070551 www.mdpi.com/journal/genesGenes 2019, 10, 551 from the Mitelman database [11]. We provided evidence that triploidy very likely initially occurs through whole genome rearrangements when one paternal genome is added to two copies of the maternal genome (XXY karyotype correlating with near-triploidy, r = 0.88, p < 0.001). Such a karyotype can be formed by a digyny-like process (Figure 1). For female tumors, this karyotype should be triploid XXX (~69XXX). A separation of parental genomes and sister chromatid non-disjunction in maternal genomes using an aberrant meiotic pathway can be presumed to occur at some stage of tumor development that involves the gametogenic reprogramming of somatic tumor cells

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