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

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.

Meta-Analysis of Cancer Triploidy: Rearrangements of Genome Complements in Male Human Tumors Are Characterized by XXY Karyotypes

“…Thus, this variant of the whole genome aberrations in triploid tumors can favor both their perpetuation and chemoresistance. More information on the evolutionary significance of digyny for adaptation to catastrophic environments and the alternation of the digyny cycle with a mitotic cycle in triploid tumors can be found in [64].…”

The Role of the Meiotic Component in Reproduction of B-RAF-Mutated Melanoma: A Review and “Brainstorming” Session

“…An interesting asexual parthenogenetic variant for triploid tumors, which are typical for resistant cancers may be achieved by digyny (69, XXY, in case of male cancers) [215]. Some observations suggest that triploidy may exchange with diploid subline on the basis of multinucleated giant cells in the same tumor [216]. The cycle of cancer stem cells likely can start with the relic uniparental disomy.…”

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics

“…This strict minority of cells can give rise to cancer relapse. The "statistically irrelevant" behaviour of cancer drug escapers is due to the change of their very nature-becoming reprogrammed to the state of an egg, embryo, or adult stem cell, thus acquiring the toti-or pluri-potency [99][100][101][102][103][104][105][106][107][108][109][110][111][112][113]. The capability of deep reprogramming particularly depends on the tp53 (tumour suppressor) insufficiency [114], which is common in the most aggressive cancers [115].…”