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

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) 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.

Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance

“…Furthermore, the connection between the mitotic slippage-induced cGAS-STING pathway and one of its targets—the transmembrane protein family Fragilis, is involved in the commitment of primordial germ cells and oogonia [ 169 , 170 ] may be also involved in this soma-to-germ transition. In summary, these current data on the CC suggest possible participation in cancer treatment resistance and provide an additional argument in support of the oldest embryonic concept of cancer with its parthenogenetic and parasexual variants [ 17 , 32 , 33 , 36 , 37 , 171 , 172 , 173 ]. Within this logic, the various requirements of the above-discussed mechanisms of resistance to anticancer treatments may be provisionally met.…”

“…However, it may also contribute via whole-genome triploid bridges [ 26 ] between diploid and tetraploid generations. A similar bridge by the doubled maternal genome was identified in a proportion of male para-triploid cancer karyotypes and in vitro on HeLa [ 32 , 33 ]. It is important to stress that polyploidy induced in cancer by genotoxic treatment cannot be reduced to only the genome multiplication and re-arrangements, but it is also accompanied by a crucial change in cell biology—the reprogramming of tumour cells to a state of embryonal stemness [ 11 , 13 , 22 , 34 , 35 , 36 , 37 , 38 ] with germline markers [ 16 , 18 , 36 , 39 , 40 , 41 , 42 ].…”

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

“…Some researchers consider a possible parthenogenetic variant of the embryological in essence theory of cancer which is known from the nineteenth century [29,213] while ontogenetic variant of this theory for the origin of tumors termed "a life-code" has been recently suggested by Jinsong Liu [214]. 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].…”

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].…”