**7. Conclusion**

*Melanoma*

and not the least, it can count homologous chromosome pairs, to get rid of aneuploidy. Strikingly, IM was revealed in the proportion of normal human oocytes sorting out the aneuploid embryos in a polar body [222]. Although SC is not needed, however the telomere clustering at the spindle pole body for the chromosome homology search by spinning the chromosomes, for DNA recombination between homologs, is needed. Although currently the study of IM in human cancer is in infancy [62], the IM related to telomere DSBs well fits several peculiarities found in tumors: cellular senescence linked to telomere attrition, polyploidy associated with cellular senescence, mitotic slippage, reprogramming, and alternative telomere lengthening characteristic for some cancers [62]. We proposed a hypothesis that ALT-associated PML bodies in mitotic slippage of tumor cells may serve as a site for IM recombination repair [177]. Interestingly, the meiotic genes involved in the homology search and recombination RAD21L (Rec8 paralog) and Hop2-Mnd1 heterodimer (RAD51-dependent) were found associated with ALT [178, 179]. The expression of the proteins, which may be involved in IM-related ALT (SPO11, MOS, TRF2-colocalised with PML-bodies), and mitotic slippage were also observed in polyploidy cells of B-RAF V600E mutant melanoma SkMel28 cell line treated with doxorubicin and vemurafenib (mutated B-RAF-inhibitor) (**Figure 3**). The question how much the meiotic features in tumors are stochastic and how much program-directed is central for addressing the problem. The most prominent feature of cancer is adaptation to extinction by the mechanisms acquired in the evolution of life on earth. The naturally occurring tumors are found already in *Hydra* [223]. When the organisms were challenged by extinction, they have adapted to it by transient polyploidy, epigenetic plasticity, including pluripotent stemness with its bivalency of genes, intrinsically disordered proteins, and rearrangement of the nuclear architecture domains by phase transitions these epigenetic adaptations are by two orders faster than the gene mutationselection-based process would allow [224]. In accord, the expression of stemness genes, early stress response genes, epigenetic master activator CTCFL/BORIS and in particular, CT antigens genes as universal adaptors for reconstruction of the genome functional network—all these epigenetic evolutionary adaptations are found in melanoma, which are highly mortal-risky and treatment resistant in patients. At the same time, the tumor pathways are rare evolutionary attractors of the genome multi-dimensional network [225], entrapping cancer cells by the therapy resistance—only a small number of cells, but inevitably survive and repopulate the tumors [56, 177]. These rare genome space states can be only chosen by the mechanisms of nonequilibrium thermodynamics, which is by coherating fluctuations, through the method of trial and error [224, 226]. Those are inevitably accompanied by a lot of cell death and a lot of aberrant phenotypes, which may persist as transient or axillary to reproductive cancer cell line. The fidelity of the genome achieved through the evolutionary meiosis and ploidy life cycles can counteract the aneuploidy; otherwise, tumor cells may balance between both options. The snap-shot studies, not considering this factor (e.g., the productive expression of meiotic genes in only sub-population of tumor cells) can thus bring to misleading interpretations [227]. Moreover, both forward and reverse mutations occurring by gene conversion were recently found in the oldest (from 1951) human cancer cell line cervical carcinoma HeLa [228], which is also known serving a positive control for the meiotic proteins antibodies and expresses them in reversible polyploidy cycles [31]. As suggested by Maciver in 2016 [229], gene conversion in asexual polyploid species can compensate the "Muller's Ratchet." Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion event. In this case, the nonreciprocal "copy-paste" recombination is occurring which is stimulated by

**104**

The CT antigens and meiotic genes enhanced expression in tumors, including B-RAF-mutant melanoma, is associated with poor prognosis for the patient survival and treatment outcomes. The review shows that the functions of CTA and meiotic genes in cancer are multilayered: they involve genetic, whole-genomic, cytogenetic, epigenomic, and posttranslational levels of regulation, which are evolutionarily evolved. That means that the expression of CT antigens and meiotic genes is in general adaptive, explaining the correlation of this expression with poor melanoma prognosis. The matter concerns some recently acknowledged biological processes, whose mechanisms and thermodynamics are not fully understood. These are reversible polyploidy and reversible senescence, transient ALT, gene conversion, and likely also several forms of evolutionary, nonconventional, asexual meiosis and parthenogenesis. The fidelity of the genome aimed through the evolutionary meiosis and ploidy life cycles can potentially compensate the aneuploidy, or the tumor cells may balance between the advantages and disadvantages of both options [150]. All these questions still remain open for future studies.

#### **Acknowledgements**

The authors thank Olga Anatskaya (St. Petersburg) for advice in bioinformatic methodology and Madara Kreismane for technical support for manuscript preparation. This work was supported by a grant from the European Regional Development Fund (ERDF) projects No. 1.1.1.1/18/A/099, 1.1.1.2/VIAA/3/19/463 for K.S. and

Student Scholarship from the University of Latvia Foundation to N.M.V.
