Open access peer-reviewed chapter

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

Written By

Dace Pjanova, Ninel M. Vainshelbaum, Kristine Salmina and Jekaterina Erenpreisa

Submitted: 12 May 2020 Reviewed: 19 August 2020 Published: 30 September 2020

DOI: 10.5772/intechopen.93641

From the Edited Volume

Melanoma

Edited by Ahmed Lasfar and Karine Cohen-Solal

Chapter metrics overview

618 Chapter Downloads

View Full Metrics

Abstract

The ectopic expression of cancer testis (CT) antigens and classic meiotic genes is characteristic and a hallmark of poor prognosis of melanoma disease. Here the potential mechanisms of meiotic influence on the cell and life cycle of malignant melanoma are reviewed in the genetic, epigenetic, and evolutionary aspects. The involved mutant B-RAF and N-RAS-induced senescence may be reversed by reprogramming, with stemness linked to meiotic landscape, possibly induced by DNA double-strand breaks at the mutual telomere hot spots. The induced by senescence mitotic slippage (reset of interphase from arrested metaphase) and resulting polyploidy trigger the meiotic ploidy cycle to function for effective DNA recombination repair, genome reduction, and escape of survivors, which enter the mitotic cycle again. The aberrant meiotic pathway in cancer is reviewed in the ancestral asexual variants; inverted meiosis is possible. The conundrum of cancer aneuploidy paradox, selection of fit clones, and the Muller’s Ratchet of inevitable accumulation of harmful mutations is discussed. The bioinformatic study of the densely connected protein interaction network of CT antigen expressed genes revealed the melanomagenesis attractor composed of PRAME and small MAGEA group in primary tumors as compared with B-RAF-mutant nevi, restructured stemness network; invasive melanoma further displays the leading role of SPANX CT antigen group; meiotic genes are expressed in all three tissue cohorts.

Keywords

  • B-RAF-mutant melanoma
  • reversible senescence
  • reversible polyploidy
  • DSB hot spots
  • ancestral meiosis

1. Introduction

Approximately 50% of melanomas carry mutations in the gene encoding B-RAF [1]. Ninety percent of activating B-RAF mutations affect the codon 600 and the most common missense change there is V600E [2]. This mutation leads to a constitutive activation of B-RAF, and consequently of the MAPK/ERK pathway, promoting survival and proliferation of melanoma cells. Other frequent mutations in melanoma include N-RAS gene, which is estimated to be present in 13–25% of melanomas [1], and being upstream of the same MAPK/ERK signal transduction pathway. The MAPK/ERK signal transduction pathway involves a signaling cascade initiated by the binding of growth factors or cytokines to their respective receptors, resulting in activation of RAS, which then recruits RAF proteins, a family of protein kinases including B-RAF, to the cell membrane. Phosphorylation of RAF allows the activation of MEK1 [MAP kinase/extracellular signal-regulated kinase 1(ERK1)], which positively regulates the extracellular signal-regulated kinases (ERK). ERK can then directly phosphorylate downstream transcription factors, leading to increased transcription and eventual cell growth and proliferation [3]. Following the discovery of the V600E mutation, the pathway targeting inhibitor drugs was developed [4, 5, 6, 7, 8, 9, 10]. However, while initial responses are impressive, therapeutic resistance develops in nearly every patient at a median of 11–15 months of treatment [6, 7, 9, 11, 12].

Human nevi (benign lesions of melanocytes) also frequently harbor V600E mutation in B-RAF [13]; however, in spite of the oncogenic nature of this mutation [14], they display classical characteristics of senescence [15] and remain benign in the large majority of cases. At the same time, nevi are supposed to give rise to a quarter of all melanomas [16]. This led to the concept that oncogene induced senescence (OIS) precedes transformation [15, 17, 18], in particular if induced by mutant RAS or B-RAF. The expression of mutant RAS in normal human tissues inducing cell proliferation arrest was first described in [19] and further widely used as a model of OIS in normal cells. For a long time, OIS as well as senescence induced either by chemotherapy or oxidative stress (so called accelerated senescence ACS) were assumed as a barrier in premalignant tumor for tumor progression [20]. However, later it was found that senescence has also an opposite side and can reverse, so promoting cancer and metastases development [21, 22, 23, 24]. Moreover, the cells that have experienced and evaded cellular senescence are more resistant to therapy than their counterparts [25]. The same group showed also that two different types of histone H3 lysine 9 (H3K9) demethylases, the flavin-dependent amine oxidase LSD1 and the 2-oxoglutarate-dependent Jumonji C family member JMJD2C, epigenetically disable oncogenic RAS- or B-RAF-induced senescence by enabling the expression of E2F target genes, which permits restarting of proliferation cycles. In turn, the inhibition of the H3K9 demethylases restores senescence and controls tumor growth of melanoma [26]. These experiments show the important contribution of the chromatin remodeling in OIS and cancer.

Biochemically, B-RAF has the same kinase activity as the serine-threonine protein kinase MOS [27] that is the main meiotic kinase [28]. Interestingly, proto-oncogenes c-ras and c-raf also participate in gametogenesis and when overexpressed (even non-mutant) can impose the meiotic mechanisms onto somatic cells [29]. In tumors, this pathway elaborating MOS-kinase can be triggered from mitosis through DNA damage checkpoint and senescence, supposedly providing them with the survival advantage [30, 31, 32, 33]. At the same time, the expression of many germline proteins specific for meiotic prophase has been found upregulated in cancers [34, 35, 36] and in melanoma [37] as well.

Below we review the literature data of the abovementioned meiosis-associated processes and pathways involved in cancer (in the wide sense) and melanoma, in particular.

Advertisement

2. Senescence, TP53 function, and polyploidy in melanoma

Melanomas often derive from nevi, which already contain oncogenic B-RAF and N-RAS mutations. It was shown in several works that the melanoma genesis from these nevi is associated with the reverse of the OIS induced by these mutations. The mutual feature for all kinds of ACS (OIS, drug-, and oxidative stress-induced) is the introduction of DNA double-strand breaks (DSBs); a persistent DNA damage signaling was shown triggering senescence [38]. The response to the latter includes the activity of tumor suppressor transcription factor p53. Dysfunction of p53 is generally associated with malignant tumors and also with associated overcoming the polyploidy barrier [39]. In relation to melanoma, these issues will be briefly considered below. Wild-type (WT) p53 that is present at undetectable levels in normal tissues, when upregulated by DNA damage, is a potent inducer of apoptosis, cell cycle arrest, and cellular senescence, in general counteracting carcinogenesis [40], but also caring for stem cells by causing transient alternative splicing of POU5F1 in senescent embryonal carcinoma until the repair of DNA damage [41]. The tumor suppressor TP53 is mutated in its DNA binding domain in about half of somatic cancers [42]. In other cases, it is also mostly inactivated in other ways, e.g., by promoter methylation, etc. [43]. TP53 mutants, however, acquire additive functions, e.g., invasive features [44]. Melanoma is not an exclusion: with approximately only 10–19% disabling point mutations, WT p53 is found inactivated in approximately 90% of cases [45, 46]. The low frequency of p53 mutation in melanoma may be due to the overexpression of its counterpart oncoprotein MDM2, which is due to inactivation of CDKN2A locus encoding the dual tumor suppressors p16INK4A and p14ARF. Likewise, the most common somatic mutations associated with familial melanoma also disrupt the CDKN2A locus [47]. In the presence of oncogenic activation (B-RAF or N-RAS), p14ARF acts to directly inhibit MDM2, the major ubiquitin ligase that normally degrades and inactivates p53 [48]. The cooperation of B-RAF mutations with nonfunctional p53 in melanoma genesis was modeled by Patton and colleagues [49] in p53-deficient Zebrafish, where activated B-RAF induced formation of melanocyte lesions rapidly developed into invasive melanomas, resembling human melanomas and could be serially transplanted. Another tumor suppressor PTEN may also participate in melanoma genesis from B-RAF V600E nevi [50]. TP53 is a barrier to polyploidy [39], the latter is often reached by mitotic slippage (reset of interphase from arrested metaphase with a tetraploid genome). Mitotic slippage and thus polyploidization accompanies OIS or irradiation-drug-induced senescence in tumors with characteristic DNA damage response [51]; however, both senescence and polyploidy, induced by OIS or genotoxic treatments, can be reversed [52, 53, 54, 55]. In this prolonged process occupying 7 and more days, the majority of giant cells succumb and the proportion of escape (de-polyploidized) cells may be rather low [56, 57] but they repopulate the tumor in the remote period of time. Mitotic slippage and DNA re-replication resulting in polyploidization was modeled in melanoma by Aurora A-kinase interference [58]. The DNA re-replication stress resulting in the fold-increased amount of DNA DSBs in the polyploidized cells was revealed. MDM2 antagonists relieved it by restoring the functional p53 and its downstream p21, interrupting re-replication of cells. Finally, the same was shown in melanoma: the experiments with prolonged expression of the oncogene N-RAS Q61K in pigment cells showed the induction of senescent multi-nucleated polyploid cells, however further overcoming OIS by the emergence of tumor-initiating mononucleated (de-polyploidized) stem-like cells from senescent cells. This progeny was dedifferentiated, highly proliferative, and anoikis-resistant, and induces fast-growing, metastatic tumors [59].

Besides inducing OIS, N-RAS and B-RAF-activating mutations can potentially impose meiotic features onto melanocytes (substituting by overexpressed B-RAF of meiotic MOS-MEK-kinase or alternatively triggering its pathway). The possibility of imposing the meiotic (oocyte maturation) program by overexpressed RAS and RAF onto somatic cells was reported in literature [29, 60, 61]. Such trigger can supposedly favor the reduction division of polyploidized tumor cells [31, 32, 33] and likely also, in collaboration with REC8, the monopolar spindle of meiotic prophase [62]. In irradiated lymphoma cell lines, MOS was activated through polyploidy only in TP53-mutants, not their WT TP53 counterparts [30], where neither polyploidy nor MOS was induced. MOS protein was shown expressed in 20 types of cancer, including melanoma (https://www.proteinatlas.org/ENSG00000172680-MOS/pathology). As shown by more recent data on OIS in melanoma [58], the persistence of DNA damage in the absence of p53 function may be a bridge to invasive melanoma. And the persistent DNA DSBs in senescing polyploid cells, in turn, may be also a bridge from the G2M DNA damage checkpoint and/or mitotic slippage to the meiotic-type recombinative prophase possessing the same molecular background [33] (see also below in the section about SPO11 nuclease). So, B-RAF and N-RAS mutation, senescence with DDR signaling, deficiency of p53 function (upregulation of MDM2), induced and reversible polyploidy, and trigger to meiotic prophase are all molecularly related and this network can be potentially involved in melanoma genesis.

Advertisement

3. Cancer testis (CT) genes

CT genes were first defined as a group of tumor antigens that elicit a cytosolic T cell response and are expressed in male germ cells in the testis and various malignancies [63, 64, 65]. The first CT antigen identified was melanoma antigen 1 (MAGEA-1) [66]. Using the melanoma cell line MZ2-MEL and autologous cytotoxic T-lymphocyte (CTL) clones cytolytic to this line, MAGE-1 (subsequently re-named as MAGEA1, melanoma antigen A1) was identified as the target antigen for one of the CTL clones. This represented the first immunogenic tumor antigen shown to have elicited autologous cytotoxic T-lymphocyte responses in a cancer patient. Pursuing the same strategy, a range of other tumor-antigen genes, including MAGE-A3, another member of the MAGE-A family, as well as two additional families of antigens, namely the BAGE and GAGE gene families, were identified [64, 67, 68, 69]. The next huge step toward the identification of tumor antigens came from the screening of cDNA expression libraries with antibodies, the technology called SEREX (serological analysis of cDNA expression libraries) [70]. Very soon SEREX led to the identification of several categories of tumor antigens. To date, more than 80 families of CT genes are recognized and defined as germline restricted genes with evaluated expression in cancer [71]. As per today’s definition, CT gene should simply exhibit a biased expression in the testis, ovaries [72], or the placenta [73], and in cancer.

CT genes can be divided between those that are encoded in the X chromosome (CT-X genes) and those that are distributed throughout the genome (non-X CT genes). CT-X genes are mostly members of gene families organized into complex direct and inverted repeats, and are expressed in testes primarily during the spermatogonial stage of spermatogenesis [74]. Annotation of the sequence of the human X chromosome has revealed that as many as 10% of all genes present on the chromosome are members of known CT families [75]. Further analysis of the expression patterns of genes of unknown function located in these repeated regions could even increase this estimate [76]. Melanoma has been found to have one of the highest CT antigens frequency expressions among other cancers. Moreover, higher frequency of CT antigens expression in melanoma is also correlated with worse disease outcome [77, 78, 79, 80].

Our analyses of the NCBI’s Gene Expression Omnibus [81] GSE98394 dataset including a cohort of 27 B-RAF-mutant nevi and 51 melanoma, described in details in [81] revealed the stark upregulation of many CT antigens in primary melanoma compared to nevi (Appendix Table 1). The densely connected component of protein-protein interactions (PPI) network of the upregulated melanoma CT antigens genes constructed using String Server [82] revealed the melanoma network module composed of 25 nodes, with a carcass of MAGEA-group hubs connected with the cohesin subunit SA-2 (STAG2) and the inhibitor of the differentiation-inducing retinoid acid receptor (PRAME) [83] hubs indicating to the acquired stemness (Figure 1). The high average node connectivity degree (5.84, PPI enrichment p-value <1.0e-16) characterizes this module as a CT antigen attractor of melanoma genesis from B-RAF-mutant nevi.

Figure 1.

The densely connected component of protein-protein interactions (PPI) network of the upregulated melanoma CT antigens constructed using String server [82].

Similar upregulation of many CTA, however, different from those, occurs when the primary melanoma progresses and metastasis are formed as revealed in the TCGA-SKCM dataset that includes 103 primary melanoma and 368 melanoma metastases (https://www.cancer.gov/tcga) (Appendix Table 2).

The biological role of CT genes, particularly CT-X genes (a majority of them are CT antigens), in both germline tissues and tumors remains not well understood. However, studies have provided some evidence that MAGE gene expression may protect cells from programmed cell death and contribute to the development of malignancies by promoting survival [84]. It has also been shown that MAGE A2 is a strong inhibitor of the p53 tumor suppressor through histone deacetylase (HDAC)3 recruitment. In human primary melanoma cells, Mage A2 expression confers resistance to chemotherapeutic drugs by interfering with p53 acetylation [85]. Mage A2 interferes with p53 acetylation at promyelocytic leukemia (PML)-nuclear bodies (NBs) and with PMLIV-dependent activation of p53 through an HDAC-dependent mechanism, so downregulating it [86]. Usually, p53 is recruited to PML-NBs where it becomes acetylated and activated, and participates in the triggering of cellular senescence [87], a critical barrier against cell transformation (discussed above).

The mechanisms involved in the regulation of CT antigens expression appears to be promoted by DNA demethylation. Methylation of CpG islands within gene promoters is responsible for gene silencing due to both its effect on chromatin structure and binding of transcription factors [88]. “Epigenetic reprogramming,” consisting of concerted DNA pan-demethylation and corresponding chromatin remodeling, occurs twice in the human life cycle: during early embryogenesis and gametogenesis of primordial germ cells (PGC) [89]. So far, all CT antigens studied have methylated CpG islands in normal somatic tissues and are activated by demethylation during spermatogenesis [90]. Experimental demethylation of CT antigens promoters induces antigen expression in cells that do not normally produce them [91]. It has been proposed that the activation of CT antigens in cancer is a consequence of the ectopic induction of gametogenic program [74, 92, 93], which thus includes the meiotic component.

As recently found, all MAGEs contain a conservative E-ring domain and assemble with E3 RING ubiquitin ligases to form MAGE-RING ligases (MRLs) that act as regulators of ubiquitination by modulating E-ring-ligase activity [94]. The latter are acting at the cross-roads between tumor suppression and oncogenesis [95]. In addition, a majority of the CT antigens [96, 97] are intrinsically disordered proteins (IDPs). IDPs lack rigid 3D structures either along their entire length or in localized regions. Despite the lack of structure, most IDPs can transit from disorder to order upon binding to various biological targets [98]. Protein intrinsic disorder can serve as the structural basis for hub protein promiscuity; thus, CT antigens proteins can provide flexible linkers between functional domains [99]. Many normal cellular processes are associated with the presence of the right amount of precisely activated IDPs at right places and at the right time, those may be altered in disease, including cancer [100, 101]. The IDPs—features of the X-linked CT antigen-encoded genes, which can change their targets, as well as the relation of the MAGE group to ubiquitin-ligases suggest their highly adaptive post-translation functions for the cancer genome and proteome networks. This property is consistent with their activation by CTCF inhibitor and pan-genome activator, the CT gene Brother of Regulator of Imprinted Sites (BORIS) located at the chromosome region 20q13.2. This region is commonly amplified in human cancers [102, 103]. BORIS expression is normally restricted to testis and becomes aberrantly expressed in different types of cancer [104]. In melanoma, BORIS expression was observed in 59% of melanoma cell lines, in 16% of primary melanomas and in 34% of melanoma metastases [105].

Normally, BORIS plays a major role in regulating de-repressing, de-methylation processes during spermatogenesis—it removes imprinting from genes during the last mitotic division of type B spermatogonia producing the first spermatocyte [106]. In particular, in melanoma, BORIS binds near the promoter of transforming growth factor-beta 1 (TFGB1), a well-recognized factor involved in the transition toward an invasive state, activating it through transcriptional reprogramming [107]. BORIS is a paralog and antagonist of CTCF. A primary role for CTCF in the global organization of chromatin architecture was shown, which suggests that CTCF may be a heritable topological repressive component of an epigenetic system regulating the interplay between DNA methylation, higher-order chromatin structure, and lineage-specific gene expression [108, 109]. Nowadays, multiple studies have indicated an oncogenic role for BORIS [110, 111, 112]. Notably, emerging evidence has shown that BORIS functions as an epigenetic modifier in modulating the whole genome gene expression [113, 114, 115], including expression of other CT genes [116, 117]. BORIS was also found to be expressed in embryonal carcinoma, ovarian cancer [118] as well as cancer stem cell (CSC)-enriched populations isolated from epithelial cancer cells [119, 120]. The mRNA isoforms of BORIS genes are expressed in normal ovary and in the altered pattern, in epithelial ovarian cancer [121]. An association of BORIS expression with CSC-like properties was also observed [119, 120]. Moreover, it has been shown that BORIS association with the CSC-like traits occurs through the epigenetic regulation of POU5F1/OCT4 [112]. OCT4 is considered a master regulator in the maintenance of stem cell pluripotency. Many studies have demonstrated a correlation between OCT4 and CSCs in many cancers, including melanoma [122, 123, 124].

In relation to metastatic melanoma, using the TCGA database (https://www.cancer.gov/tcga), we assessed the expression of a number of genes selected from the POU, SOX, SALL, and NANOG gene families with relation to stemness in normal and cancer stem cells [125] and noted an increase in stemness during transition from primary melanoma to metastases. Moreover, the heat map shows the reconstruction of the landscape in the expression of stemness-associated genes indicating to the whole genome rearrangement (Figure 2).

Figure 2.

Gene expression (in log2CPM values) of stemness genes in the cohort of 368 melanoma metastases compared to 103 primary melanoma from the TCGA-SKCM dataset (https://www.cancer.gov/tcga). The data was extracted from the TCGA database using the TCGA Biolinks Bioconductor package [126]. EdgeR [127] was used to perform differential expression analysis through the generalized linear model approach. The differentially expressed genes (DEGs) which were upregulated in metastatic melanoma (log2FC > 0, p < 0.01) were filtered for genes from the POU, SOX, SALL, and NANOG gene families with relation to stemness. Seaborn [128] was used to construct the heat map.

Melanocytes originate from the neural crest developing in embryo very early (as the fourth germ layer) and is associated with intensive cell migration. Melanomas in patients or cell constructs upregulating the Wnt pathway, associated with neural crest development, display epithelial-to-mesenchyme-transition (EMT) phenotype, worse prognoses in patients, and resistance to drugs in vitro [129]. The role of the neural crest development factors in ectopic regulation of melanoma was also investigated in [130]. Likely, because of the origin, nearly the root of the ontogenetic tree, melanoma is so invasive and malignant.

The particular interest for carcinogenesis represents the non-X CT genes or germline restricted genes that normally mediate meiotic program [30, 34, 35, 36, 37, 131] and therefore are denoted by some authors, the meiosis-specific CT (meiCT) genes [36].

Advertisement

4. Conventional meiosis: in brief

The conventional meiotic progression is well described [28] and has been recently updated by Feichtinger and McFarlane [35]. Thus, only a short recitation of some of the main points is provided here.

Meiosis is a special mode of cell division that naturally occurs in mammalian only in the germ cells—in the male testis and female ovary. During meiosis, diploid germ cells undergo a single round of premeiotic DNA replication (4n), followed by two chromosome segregation events, meiosis I (reductional) and meiosis II (equational), creating haploid (1n) gametes. Meiosis I is marked by a prolonged prophase that is subdivided into five stages: leptotene, zygotene, pachytene, diplotene, and diakinesis, where during the first three stages, there occurs the formation of DSBs, homologous chromosome pairing, and synapsis and reciprocal homologous recombination (HR) between them. The initiation of meiosis is not fully understood in mammals, but it is thought that meiotic entry is initiated by upregulation of the stimulated by retinoic acid 8 (STRA8) gene expression—transcription activator that binds directly to the promoter regions of meiosis-specific genes [124, 125, 126].

During premeiotic DNA replication, a ring of specific cohesins is formed that holds newly formed sister chromatids together [127]. In meiosis I prophase, HR program is initiated by the generation of DNA DSBs along the chromosome axis in specific hotspots [128]. This is initiated by a protein complex, which consists of SPO11 and TOPOVIBL [129]. Generated DSBs serve as the substrates for the recombinase RAD51 and its meiosis-specific paralogue DMC1 acting as a heterodimer [130]. The hot spot selection in mammals mediates the zinc finger histone methyltransferase, PR domain containing 9 (PRDM9), which primes the DNA for DSB and exchange of DNA between chromosomes [131, 132]. Of note, in the case of meiosis, DNA DSBs are obligatory rather than the result of accidental damage, as in the mitotic cell cycle, and the recombination partners are homologous chromosomes in meiosis, whereas they are sister chromatids in DNA repair during mitosis. As the homologous chromosome bivalents after HR align on the metaphase I plate, the centromeres of sister chromatids form monopolar spindle associations. Loss of sister cohesion in the arm regions of chromosomes, but not the centromeric regions, occurs on entry into meiotic anaphase I permitting reductional segregation of homologous chromosomes. During meiosis II, centromeric cohesion is broken down and an equational segregation of the chromatids, like in mitosis, occurs [127].

Advertisement

5. Melanoma and meiosis specific CT (meiCT) genes

HR sites resulting in crossovers are initiated by the creation of DSBs in the leptotene prophase stage catalyzed by the protein Spo11 [132]. Spo11 is an homolog of the A subunit of type II DNA topoisomerase that together with TOPOVIBL, an homolog of B subunit, forms protein complex. The MREII exonuclease creates DNA nicks guiding the SPO11-TOPOVIBL complex to accurately catalyze DSBs along the genome in specific hotspots [133, 134]. Aberrant expression of SPO11 has been found in cell lines of melanoma and also lung cancer [135], see Figure 3, acute myeloid leukemia (AML) [136], cutaneous T-cell lymphoma (CTCL) [137] as well as in patient samples of melanoma, [135, 138], cervical cancer [135], gastric cancer [138], and CTCL [139]. Although the exact mechanism of SPO11 reactivation in cancer cells remains elusive, it has been shown that in CTCL, it is regulated epigenetically and temporary expressed at the onset of the cell division in G1/S phase transition [139]. This expression before DNA replication seems unrelevant but, indeed, it appears that SPO11 expression in B-RAF- and TP-53 mutant melanoma may be not dependent on the cell cycle phase (Figure 3).

Figure 3.

Meiotic genes, alternative telomere lengthening, and mitotic slippage in B-RAF V600E and TP53-mutant melanoma SkMel28 cell line: (A) the expression of the meiotic MOS-kinase (sc-28,789) and recombination endonuclease SPO11 (sc-377,161) in cell nuclei of non-treated cells; (B) co-expression of MOS and cyclin B1 (sc-245) in rare polyploid cells and some metaphases [14] of nontreated control; (C) the polyploid cell on day 7 after doxorubicine treatment (500 nM for 24 h) maintains telomeres (marked by TRF2, 05-521, millipore) by alternative lengthening of telomeres (ALT) in promyelocytic leukemia (PML) (PA5-80910, thermo fisher scientific) bodies; and (D) two giant cells resistant to B-RAF inhibitor vemurafenib (50 nM for 24 h), with signs of mitotic slippage and multinucleation on day 21 after treatment show positivity for SPO11. Bars = 10 μm.

SPO11 expression in CTCL cell lines decreased after cell line treatment with histone deacetylase (HDAC) inhibitors, e.g., Vorinostat and Romidepsin [137]. Moreover, SPO11-introduced DNA DSBs have also been shown to increase the risk of genome rearrangements and mutations in the germline [140]—a potential source of the idiopathic male infertility, which is associated with the 20-fold increased risk of the germline cancer [141]. Spo11 appears to be present in all sequenced eukaryotic genomes, and indeed it may be the only truly universal meiotic protein. At the same time, in many organisms, the recombination defect in Spo11 mutants can rescue meiosis by production of DSBs from an exogenous source such as ionizing radiation [142, 143]. On the other side, SPO11 was also found in species and tissues undergoing asexual life-cycles [143] or DNA recombination for nonsexual function. e.g., SPO11 was revealed in mouse germinal center B cells undergoing immunoglobulin gene diversification and class switch recombination, but mice lacking Spo11 had no detectable immune system defects [144]. SPO11 introduces meiotic recombination breaks in the chromosome DSB hotspots [145]. So, it is possible that senescence-associated DDR affecting the DSB hot spots (at least, in p53-nonfunctional tumors) can upregulate and attract SPO11. Localized clustered hotspots are a feature of meiotic recombination in S. pombe, mouse, and humans as well, but the factors that determine whether a given DNA sequence will be a DSB hotspot are not well understood in any organism. Such hotspots may appear due to underreplication of DNA in the heterochromatin, particularly in telomeres, e.g., in the drug-induced senescence of tumor cells [146]. Depletion of the H3K9me3 chromatin repressive hallmarks seems rather decisive for attraction of SPO11 to the hot spots [147]. This data shows that execution of the very definitive molecular biochemical mechanism of SPO11 is dependent on the permissive epigenetic chromatin organization of the very general character. Therefore, it is interesting to highlight the breaking through report showing the reset of senescence and abrogation of invasive growth achieved in melanoma by inhibition of the DNA demethylases [26].

Spo11 is the catalytic center of the meiotic recombination initiation mechanism, but it is not sufficient to generate DSBs: numerous additional proteins are also required; the main of them is Mre11-Rad50-Xrs2 (MRX). These proteins form a complex with multiple roles in many different aspects of DNA metabolism, including DNA repair, telomere maintenance, and checkpoint signaling. Mutant MRX complex leaves SPO11 accumulated to telomere ends with the nonreleased terminal chiasmata [148]. Although the SPO11 catalytic gene part is conserved, the proteins involved in meiotic recombination are generally among the more rapidly evolving of all cellular proteins: major challenges for them represent the whole genome duplications (WGDs) and the difficulties of auto- and allo-polyploids in the meiotic reduction divisions [149, 150].

The meiosis-specific histone methyltransferase gene PRDM9 has also been reported to be activated in melanoma alongside with other cancers, like embryonal carcinoma, astrocytoma, leukemia, colon, prostate, breast, and ovary cancers [151].

Another meiosis-specific gene involved in SPO11-mediated recombination regulation, TEX15, has been reported to be overexpressed in melanoma and other cancers including bladder, head and neck, and lung carcinomas, neuroblastomas, prostate tumors, and sarcomas [152].

The synapsis of homologous chromosomes in conventional meiotic prophase is marked by synaptonemal complex (SC). SC is a large zipper-like protein complex that connects one pair of sister chromatids to the homologous pair, so stabilizing the tetrad and ensuring proper homolog pairing. SC formation starts with the formation of axial element that consists from SC proteins 2 and 3 (SCP2 and SCP3). Then, the axial elements (at this point referred lateral elements) are joined by the transverse filaments formed by the SC protein 1 (SCP1) [153, 154, 155]. The central elements consists of SC central element 1 and 2 (encoded by SYCE1 and SYCE2) [156]. Notably, SYCP1 and SYCP3 genes both have been implicated in cancer. Both mRNA are expressed in a variety of cancers and cancer cell lines including melanoma [30, 31, 157, 158]. Moreover, SCP3 protein expression correlated with activated AKT (pAKT) signaling [159]. Overexpression of SCP3 was shown prognostically unfavorable for lung cancer [160].

HORMA domain containing 1 (Hormad1) is another protein associated with SC axis. It has multiple roles, but in general it coordinates DSB formation with synapsis and the timely progression of DSB repair through HR [161]. Hormad1 is significantly upregulated in several cancers and noted also in melanoma [37, 162]. Although the mechanism of its reactivation remains elusive, hypomethylation of the HORMAD1 promoter region correlates with its increased expression in breast cancer and small cell lung cancer [163, 164], suggesting at least partial involvement of epigenetic pathways.

Chromosome regulation in meiosis and in mitosis is dependent upon the cohesin complex. In mitotically dividing cells, this complex serves to hold sister chromatids until they settle in metaphase plate, becoming separated in anaphase while in conventional meiosis, sisters stay together through the whole meiosis I to ensure sister centromeres orientate to the same pole to drive the reductional segregation of bi-chromatid homologs. Although the structure of cohesin complexes involved in mitosis and meiosis is similar, the difference lies in subunit composition. In meiosis, specific paralogues of some of the cohesin proteins replace their mitotic counterparts [165]. One of the more prominent cohesin subunits that appears to be restricted to meiosis is REC8 (paralogous counterparts to the RAD21 mitotic cohesin) [165]. The upregulated expression of Rec8 protein was demonstrated in melanoma [37, 166] as well as in CTCL [139, 167], irradiated TP53-mutant lymphoma cell lines, HeLa, and breast and colon cancer cell lines [31, 168]. Recently it has been shown that REC8 imposed monopolarity of sister centromeres in mitotically dividing cells could result in uniparent disomy (UPD) at least in the model organism S. pombe (fission yeast) [169] possessing a facultative sex. REC8 in cooperation with Mos-kinase forms a monopolar spindle of octoploid lymphoma cells (after ionizing irradiation) which undergo recombination of DNA DSBs by meiotic recombinase DMC1 [62]. Interestingly, Rec8 does not appear to be incorporated into mitotic cohesin complex in HEK293 cells unless another meiosis-specific cohesin subunit, STAG3, is activated [170]. In melanoma, STAG3 as well as STAG2 (mitosis specific cohesin subunit) levels have been linked to the resistance of B-RAF inhibitors [171]. STAG cohesins also participate with CTCF in the topological suppression of transcription and it is the the reduced level of STAG3 that is associated with resistance to B-RAF inhibitors.

The cohesin-related regulators, SGO1/2 are also the meiosis-specific proteins that protect cohesin complex, in particular Rec8, from the protease separase-mediated cleavage at the centromeres of sister chromatids in meiosis I and retained Rec8 around the centromere until the start of anaphase II [172, 173, 174]. Upregulation of SGO2 expression has been demonstrated in melanoma [37] alongside with upregulation also in CTCL [139, 167] and SGO 1/2, along with REC8, in irradiated lymphoma cells [168]. However, the role of meiotic cohesins in cancer has not been extensively investigated.

Another meiosis-specific cohesin subunit, which has gene expression tightly restricted to the testis in healthy humans, is RAD21L (also RAD21/REC8 paralogue) [165]. However, it is also important for the maintenance of female fertility during natural aging [175].

While the majority of somatic cells are deficient in active telomerase, cancer cells not only can reactivate telomerase, but can also initiate a mechanism of the alternative telomere maintenance (ALT) in the absence of telomerase activity [176] or undergo transient ALT [177]. Some meiosis genes were found associated with supposed homology search in ALT [178, 179]. ALT requires a recombination-like mechanism to recognize the telomere end as DSBs and mediate the strand invasion of the end into a nonhomologous chromosome end. This strand invasion permits the initiation of a break-induced DNA replication process where the invaded non-homolog telomeric DNA serves as a replicative template for the invading telomere to elongate [180]. In summary, the review of the classic meiotic genes demonstrates their involvement in cancer, and melanoma in particular, although their function in cancer is ill defined.

Advertisement

6. Brainstorming session

“Nothing in biology makes sense except in the light of evolution”—Dobzhansky 1973 [181].

B-RAF-mutant melanoma activates MEK-ERK proliferative pathway but cancer can be explained neither only by enhanced proliferation nor it can be reduced to somatic mutation theory, which has been shaken by cancer genome sequencing projects. Cancer is more complex than that [182]. B-RAF-and N-RAS-mutant nevi remaining quiescent and benign just support this notion. A very important role of OIS-induced cellular senescence for initiation of malignant tumors discovered by Serrano et al. [19] and the role of its epigenetic landscape have been revealed in recent years. Melanoma is interesting therefore as RAS, B-RAF mutations just produce this senescent background, which can undergo reverse by reprogramming resulting in drug resistance [25], but senescence can be again restored in invasive B-RAF-mutant melanoma by structurally unrelated silencing with H3K9 de-methylases [26]. Thus, OIS senescence in cancer has a dynamic nature with the epigenetic component of the general character [183]. But melanoma is also interesting for the high overexpression of meiosis-related CT genes. Overexpression of CT antigens is prognostic for poor outcome of invasive melanoma; in addition, classic meiotic genes are known to be expressed in cancers [30, 31, 168] and also in melanoma [37]. Some authors reason that overlaying of meiotic protein aberrant activities over the normal mitotic cycle (termed “meiomitosis”), first of all of the stable cohesion of sister chromatids needed for meiosis I, is interfering with normal mitotic separation of chromatids, leading to aneuploidy, genome instability, and tumor progression [36, 37, 184, 185]. The questions arise: (1) whether the mitotic cycle in tumors is normal? (2) If the meiotic features found in tumors belong to conventional gametic meiosis? (3) If an aneuploidy can perpetuate the tumor growth? Let us begin with the latter. This problem is well known as “Aneuploidy Paradox” [186], which means that incorrect segregations of genetic material should hinder and prevent cell division; however, aneuploidy paradoxically is well known as correlating with tumor growth and aggression, which may be due to selection of the fittest aneuploid clones. This conundrum cannot be explained satisfactorily with clonal selection of rare positive mutations because the “Muller‘s Ratchet” [187] will inevitably accumulate deleterious mutation leading ultimately to extinction of the asexual cell line. The problem, of the “Muller Rachet”, however is still explored by population evolutionists [188]. Aneuploidy in cancer arises from the inherent chromosome instability of polyploidy cells. So, we arrive here to the polyploidy which in different proportions is a very characteristic feature of all malignant tumors (comparing with their normal tissue origins), progresses with cancer aggression, and which up to now is often ignored by cancer researchers [189]. However, it is just a reversible polyploidy, which provides the extraordinary resistance of cancers to therapy [56, 190, 191, 192] and likely a cancer line immortality as such. Moreover, our studies brought us to the notion of a cancer life cycle, composed of a cell cycle (lasting 17-23 h) and ploidy cycle (reversible polyploidization which takes 1–2 weeks or more), both cycles are reciprocally linked [32, 193]. This reciprocal cancer life cycle is an analogue of the “neosis” of cancer cells, related to polyploidy and senescence with rejuvenation of reduced offsprings described by Rajaraman [194, 195] and was confirmed in tumors by multiple authors [190, 191, 192], also in melanoma [59]. Thus, the answer to the first question is that the cell cycle in cancers including melanoma is not conventional and at least, in the tumor subpopulation, it is composed of two reciprocally joined different cycles, conventional mitotic and a ploidy cycle, one being quick and another being slow. The latter is often overlooked [189] as being hidden due to the low proportion in relation to the mitotic cycles. The ploidy cycle of giant cells associated with senescence reprogramming becomes clearly manifested in resistant tumors after high dosage DNA damage with anticancer drugs and ionizing irradiation [177, 196, 197, 198]. Therefore, cancer research needs prolong follow up of individual cells and ploidy measurements [177, 191, 199, 200]. Tumor cells enter this ploidy cycle when they senesce by OIS or get the DNA damage in any other way (e.g., by ionizing irradiation or oxidative stress). If the treatment is harsh, the majority of induced giant cells will die in the time course, during mitotic catastrophe or in unsuccessful attempts of multipolar or aberrant bipolar bridged mitoses, but a minor minority of resistant cancer cells repair the DNA damage and repopulate tumors through depolyploidization by budding or other type of ploidy reduction [33, 56, 189, 191, 201, 202]. So, in our brainstorming session, we arrived to ploidy cycles and DNA damage. Here is a right link to the origin of meiosis and sex. The whole genome duplications (WGD) is a well-known driver of gene and species evolution [203] and appeared already in prokaryotes as the first evolutionary steps toward eukaryotic sex [204]. The most immediate reasons of the meiosis origin were the necessity to repair DNA damage [205]. Another reason, coupled to the first, was the relief of mutational load of aneuploidy resulting from polyploidy when it was advantageous to have more than one copy of the genome per cell [206]. Thus, the aneuploidy paradox in cancer might be resolved by asexual (somatic) meiosis (including recombination and reduction) and this meiosis is very likely ancestral. Briefly, the evolution of meiosis in eukaryotes could start from polyploid endomitosis (insect-type, without actual karyotomy), (enriched in MOS-kinase as found in tumor cells) [207], followed by zygotic meiosis, and ending in gametic meiosis in most extant vertebrates [149, 208, 209, 210]. Meiosis originated in evolution several times; there is also a view that individual blocks of genetic program of meiotic regulation could evolve independently [211]. Considering the expression of CT genes not only in testis but also in ovaria, early embryo and placenta, Loyd Old [212] associated their expression with the female gametogenesis-like program in tumor cells by formulating the title of his article “Cancer is a somatic cell pregnancy.” 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]. The cycle of cancer stem cells likely can start with the relic uniparental disomy. The latter is described in facultative sex of the fission yeast [169], in plants, stressed and spontaneously [217] and in senescing human cells [218]. All these parasexual mechanisms may include aberrant meiotic elements and genes activity [62] and may exist in parallel or as a complex chain of one process of the survival support and escape of resistant tumors. In fact, their studies are only started. So, the answer to the second question if we should reckon exclusively with the mechanisms of conventional gametic meiosis in somatic tumors is also negative. SC in tumors was never found although the relevant genes and proteins ectopically expressed [62, 160], including melanoma [37]. We should rather reckon with evolutionary forms of meiosis in asexual life cycles. This turn of reasoning is becoming particularly context-updated if we also consider the recent gene expression phylostratigraphic analysis showing that ancestral regulatory networks drive cancer [219]. The latter in turn is associated with polyploidy [220]. Moreover, in recent time, the ancient inverted meiosis (IM) appeared on the stage [221]. IM does not require the cohesion of sister chromatids (thus, SC is not needed): the homologs are joined by their ends, recombine by sub-telomeric sequences, segregate sisters in the first meiosis and homologs in the second. Thus, IM can repair the damaged telomeres, provide some degree of genetic diversity, 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 mutation-selection-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 DNA strand breaks in hot spots [230]. This type of the genetic reconstruction seems also to be compatible with tumor cell senescence, mitotic slippage, and ALT.

Advertisement

7. Conclusion

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.

Advertisement

Acknowledgments

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.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

Advertisement

GeneSymbolLog2FC
Melanoma-associated antigen 3MAGEA37.645235
Melanoma-associated antigen 12MAGEA127.348702
Cancer/testis antigen 2CTAG27.111641
MAGE family member C2MAGEC26.874003
Melanoma-associated antigen 6MAGEA66.828297
Chondrosarcoma-associated Gene 1CSAG16.204377
Preferentially expressed antigen of melanomaPRAME5.821726
Melanoma-associated antigen 1MAGEA15.752684
MAGE family member A2BMAGEA2B5.738676
Melanoma-associated antigen 4MAGEA45.327805
Prostate-associated gene protein 5PAGE55.246215
Prostate-associated gene protein 2PAGE24.905513
MAGE family member B2MAGEB24.803597
Melanoma-associated antigen 11MAGEA113.985815
PAGE family member 2BPAGE2B3.714482
MAGE family member C1MAGEC13.522569
Melanoma-associated antigen 10MAGEA103.168079
Cancer/testis antigen family 25, member 1aDSCR82.770747
Interleukin 13 receptor subunit alpha 2IL13RA22.338307
TransgelinTAGLN2.28783
Catenin alpha 2CTNNA22.112868
Mesenteric estrogen-dependent adipogenesisMEDAG2.087961
PDZ binding kinasePBK2.022606
Homeobox protein BarH-like 1BARX11.99113
Centrosomal protein 55CEP551.86278
Sperm-associated antigen 4SPAG41.521662
T-cell activation RhoGTPase activating proteinTAGAP1.510325
MAGE family member B17MAGEB171.498956
Homeobox protein ARXARX1.147917
Outer dense fiber of sperm tails 3BODF3B1.144663
ATPase family AAA domain containing 2ATAD21.116308
MAGE family member D1MAGED10.941916
GATA zinc finger domain containing 2AGATAD2A0.892566
ADAM metallopeptidase domain 28ADAM280.838868
Phosphotyrosine picked threonine-protein kinaseTTK0.78873
Opa-interacting protein 5OIP50.775664
Acrosin binding proteinACRBP0.518623
Nucleolar protein 4 likeNOL4L0.487608
GATA zinc finger domain containing 2BGATAD2B0.484958
Outer dense fiber of sperm tails 2ODF20.40552
MAGE family member F1MAGEF10.334573
Cancer/testis antigen 101KIAA01000.315249
Transgelin 2TAGLN20.241303
DDB1- and CUL4-associated factor 12DCAF120.228037

Appendix Table 1.

The list of genes with significantly upregulated expression of CT antigenes in the cohort of 51 primary melanomas compared to 27 B-RAF V600E-mutant nevi from the NCBI’s Gene Expression Omnibus GSE98394 dataset (described in detail in [80]). EdgeR [127] was used to perform differential expression analysis through the generalized linear model approach. The differentially upregulated in melanoma genes (log2FC > 0, p < 0.01) were filtered for CT antigenes. The whole CT antigenes list comprising of 220 genes was acquired from the CT database [70]. Expression is presented as log2 FC units.

GeneSymbolLog2FC
SPANX family member A2SPANXA24.748924
SPANX family member B1SPANXB14.617090
Sperm protein associated with the nucleus, X-linked, family member A1SPANXA14.501381
Transgelin 3TAGLN34.426952
SPANX family member DSPANXD3.947176
Transmembrane protein with EGF-like and two follistatin-like domains 2TMEFF23.767568
SPANX family member CSPANXC3.684016
Interleukin 13 receptor subunit alpha 2IL13RA22.558249
Coiled-coil domain containing 33CCDC332.399770
PAGE family member 4PAGE42.248496
Nucleolar protein 4NOL42.078128
Tudor domain containing 15TDRD151.896378
VENT homeobox pseudogene 1VENTXP11.859120
DDB1 and CUL4 associated factor 12 like 2DCAF12L21.816185
SPANXA2 overlapping transcript 1SPANXA2-OT11.793161
RNA binding motif protein 46RBM461.765131
F-box protein 39FBXO391.599419
ADAM metallopeptidase domain 28ADAM281.545184
T cell activation RhoGTPase activating proteinTAGAP1.530934
Tektin 5TEKT51.443142
Maelstrom spermatogenic transposon silencerMAEL1.415596
Actin-like 8ACTL81.358688
MAGE family member A1MAGEA11.315031
ADAM metallopeptidase domain 21ADAM211.210916
PRAME N-terminal-like, pseudogenePRAMENP1.202568
MAGE family member A10MAGEA101.163532
MAGEA10-MAGEA5 readthroughMAGEA10-MAGEA51.163181
NLR family pyrin domain containing 4NLRP41.053507
ADAM metallopeptidase domain 22ADAM220.922948
Acrosin binding proteinACRBP0.854224
Transmembrane protein 108TMEM1080.793037
Ankyrin repeat domain 45ANKRD450.779239
BAGE family member 2BAGE20.733106
Mesenteric estrogen dependent adipogenesisMEDAG0.72858
Sperm associated antigen 4SPAG40.70602
Placenta enriched 1PLAC10.669653
Fetal and adult testis expressed 1FATE10.61294
Transmembrane protein with EGF-like and two follistatin-like domains 1TMEFF10.603075
Piwi-like RNA-mediated gene silencing 4PIWIL40.601545
Piwi-like RNA-mediated gene silencing 2PIWIL20.566213
Centrosomal protein 290CEP2900.489041
Stromal antigen 2STAG20.470227
Cutaneous T cell lymphoma-associated antigen 1CTAGE10.457364
SSX family member 2 interacting proteinSSX2IP0.426617
TransgelinTAGLN0.425961
MSANTD3-TMEFF1 readthroughMSANTD3-TMEFF10.423834
Tudor domain containingTDRD60.344416
ATPase family AAA domain containing 2ATAD20.322527
TTK protein kinaseTTK0.316241
ATPase family AAA domain containing 2BATAD2B0.30301
Stromal antigen 1STAG10.277385
OIP5 antisense RNA 1OIP5-AS10.26571
M-phase phosphoprotein 10MPHOSPH100.235959
DDB1- and CUL4-associated factor 12DCAF120.158102

Appendix Table 2.

Significantly upregulated expression of CT antigenes in the cohort of 368 melanoma metastases compared to 103 primary melanomas from the TCGA-SKCM dataset (https://www.cancer.gov/tcga). The data was extracted from the TCGA database using the TCGA Biolinks Bioconductor package [124]. EdgeR [127] was used to perform differential expression analysis through the generalized linear model approach and the differentially expressed genes (DEGs) which were upregulated in metastatic melanoma (log2FC > 0, p < 0.01) were filtered for CT antigens. The CT antigenes list comprising of 220 genes was acquired from the CT database [70]. Expression is presented as log2FC units.

References

  1. 1. Network TCGA. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681-1696. DOI: 10.1016/j.cell.2015.05.044
  2. 2. Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. Journal of Translational Medicine. 2012;10:85. DOI: 10.1186/1479-5876-10-85
  3. 3. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochimica et Biophysica Acta. 2007;1773(8):1263-1284. DOI: 10.1016/j.bbamcr.2006.10.001
  4. 4. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. The New England Journal of Medicine. 2010;363(9):809-819. DOI: 10.1056/NEJMoa1002011
  5. 5. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. The New England Journal of Medicine. 2012;367(2):107-114. DOI: 10.1056/NEJMoa1203421
  6. 6. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet (London, England). 2015;386(9992):444-451. DOI: 10.1016/s0140-6736(15)60898-4
  7. 7. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England Journal of Medicine. 2011;364(26):2507-2516. DOI: 10.1056/NEJMoa1103782
  8. 8. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: A phase 1 dose-escalation trial. Lancet (London, England). 2012;379(9829):1893-1901. DOI: 10.1016/s0140-6736(12)60398-5
  9. 9. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: A multicentre, open-label, phase 3 randomised controlled trial. Lancet (London, England). 2012;380(9839):358-365. DOI: 10.1016/s0140-6736(12)60868-x
  10. 10. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. The New England Journal of Medicine. 2012;366(8):707-714. DOI: 10.1056/NEJMoa1112302
  11. 11. Johnson DB, Sosman JA. Therapeutic advances and treatment options in metastatic melanoma. JAMA Oncology. 2015;1(3):380-386. DOI: 10.1001/jamaoncol.2015.0565
  12. 12. Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, phase 3 trial. The Lancet Oncology. 2016;17(9):1248-1260. DOI: 10.1016/s1470-2045(16)30122-x
  13. 13. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, et al. High frequency of BRAF mutations in nevi. Nature Genetics. 2003;33(1):19-20. DOI: 10.1038/ng1054
  14. 14. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-954. DOI: 10.1038/nature00766
  15. 15. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436(7051):720-724. DOI: 10.1038/nature03890
  16. 16. Bevona C, Goggins W, Quinn T, Fullerton J, Tsao H. Cutaneous melanomas associated with nevi. Archives of Dermatology. 2003;139(12):1620-1624; discussion 1624. DOI: 10.1001/archderm.139.12.1620
  17. 17. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Tumour biology: Senescence in premalignant tumours. Nature. 2005;436(7051):642. DOI: 10.1038/436642a
  18. 18. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436(7051):725-730. DOI: 10.1038/nature03918
  19. 19. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593-602. DOI: 10.1016/s0092-8674(00)81902-9
  20. 20. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130(2):223-233. DOI: 10.1016/j.cell.2007.07.003
  21. 21. Sabisz M, Skladanowski A. Cancer stem cells and escape from drug-induced premature senescence in human lung tumor cells: Implications for drug resistance and in vitro drug screening models. Cell Cycle (Georgetown, Texas). 2009;8(19):3208-3217. DOI: 10.4161/cc.8.19.9758
  22. 22. Angelini PD, Zacarias Fluck MF, Pedersen K, Parra-Palau JL, Guiu M, Bernadó Morales C, et al. Constitutive HER2 signaling promotes breast cancer metastasis through cellular senescence. Cancer Research. 2013;73(1):450-458. DOI: 10.1158/0008-5472.can-12-2301
  23. 23. Campisi J. Aging, cellular senescence, and cancer. Annual Review of Physiology. 2013;75:685-705. DOI: 10.1146/annurev-physiol-030212-183653
  24. 24. Erenpreisa J, Salmina K, Cragg MS. Accelerated senescence of cancer stem cells: A failure to thrive or a route to survival? In: Dorszewska J, Kozubski W, editors. Senescence—Physiology or Pathology. London UK: IntechOpen; 2017. p. 18. DOI: 10.5772/intechopen.68582
  25. 25. Milanovic M, Fan DNY, Belenki D, Däbritz JHM, Zhao Z, Yu Y, et al. Senescence-associated reprogramming promotes cancer stemness. Nature. 2018;553(7686):96-100. DOI: 10.1038/nature25167
  26. 26. Yu Y, Schleich K, Yue B, Ji S, Lohneis P, Kemper K, et al. Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma. Cancer Cell. 2018;33(2):322-336.e328. DOI: 10.1016/j.ccell.2018.01.002
  27. 27. Chadee DN. Involvement of mixed lineage kinase 3 in cancer. Canadian Journal of Physiology and Pharmacology. 2013;91(4):268-274. DOI: 10.1139/cjpp-2012-0258
  28. 28. Kleckner N. Meiosis: How could it work? Proceedings of the National Academy of Sciences of the United States of America. 1996;93(16):8167-8174. DOI: 10.1073/pnas.93.16.8167
  29. 29. Erenpreiss JO. Current Concepts of Malignant Growth. Part a. from a Normal Cell to Cancer. Riga: Zvaigzne; 1993
  30. 30. Kalejs M, Ivanov A, Plakhins G, Cragg MS, Emzinsh D, Illidge TM, et al. Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe. BMC Cancer. 2006;6:6. DOI: 10.1186/1471-2407-6-6
  31. 31. Ianzini F, Kosmacek EA, Nelson ES, Napoli E, Erenpreisa J, Kalejs M, et al. Activation of meiosis-specific genes is associated with depolyploidization of human tumor cells following radiation-induced mitotic catastrophe. Cancer Research. 2009;69(6):2296-2304. DOI: 10.1158/0008-5472.can-08-3364
  32. 32. Erenpreisa J, Cragg MS. MOS, aneuploidy and the ploidy cycle of cancer cells. Oncogene. 2010;29(40):5447-5451. DOI: 10.1038/onc.2010.310
  33. 33. Erenpreisa J, Cragg MS. Three steps to the immortality of cancer cells: Senescence, polyploidy and self-renewal. Cancer Cell International. 2013;13(1):92. DOI: 10.1186/1475-2867-13-92
  34. 34. Nielsen AY, Gjerstorff MF. Ectopic expression of testis germ cell proteins in cancer and its potential role in genomic instability. International Journal of Molecular Sciences. 2016;17(6):890. DOI: 10.3390/ijms17060890
  35. 35. Feichtinger J, McFarlane RJ. Meiotic gene activation in somatic and germ cell tumours. Andrology. 2019;7(4):415-427. DOI: 10.1111/andr.12628
  36. 36. Gantchev J, Martínez Villarreal A, Gunn S, Zetka M, Ødum N, Litvinov IV. The ectopic expression of meiCT genes promotes meiomitosis and may facilitate carcinogenesis. Cell Cycle (Georgetown, Texas). 2020;19(8):837-854. DOI: 10.1080/15384101.2020.1743902
  37. 37. Lindsey SF, Byrnes DM, Eller MS, Rosa AM, Dabas N, Escandon J, et al. Potential role of meiosis proteins in melanoma chromosomal instability. Journal of Skin Cancer. 2013;2013:190109. DOI: 10.1155/2013/190109
  38. 38. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature Cell Biology. 2009;11(8):973-979. DOI: 10.1038/ncb1909
  39. 39. Aylon Y, Oren M. p53: Guardian of ploidy. Molecular Oncology. 2011;5(4):315-323. DOI: 10.1016/j.molonc.2011.07.007
  40. 40. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Research. 1991;51(23 Pt 1):6304-6311
  41. 41. Baryshev M, Inashkina I, Salmina K, Huna A, Jackson TR, Erenpreisa J. DNA methylation of the Oct4A enhancers in embryonal carcinoma cells after etoposide treatment is associated with alternative splicing and altered pluripotency in reversibly senescent cells. Cell Cycle (Georgetown, Texas). 2018;17(3):362-366. DOI: 10.1080/15384101.2018.1426412
  42. 42. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harbor Perspectives in Biology. 2010;2(1):a001008. DOI: 10.1101/cshperspect.a001008
  43. 43. Kastan MB. Wild-type p53: Tumors can't stand it. Cell. 2007;128(5):837-840. DOI: 10.1016/j.cell.2007.02.022
  44. 44. Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170(6):1062-1078. DOI: 10.1016/j.cell.2017.08.028
  45. 45. Hocker T, Tsao H. Ultraviolet radiation and melanoma: A systematic review and analysis of reported sequence variants. Human Mutation. 2007;28(6):578-588. DOI: 10.1002/humu.20481
  46. 46. Box NF, Vukmer TO, Terzian T. Targeting p53 in melanoma. Pigment Cell & Melanoma Research. 2014;27(1):8-10. DOI: 10.1111/pcmr.12180
  47. 47. Potrony M, Badenas C, Aguilera P, Puig-Butille JA, Carrera C, Malvehy J, et al. Update in genetic susceptibility in melanoma. Annals of Translational Medicine. 2015;3(15):210. DOI: 10.3978/j.issn.2305-5839.2015.08.11
  48. 48. Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, et al. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. The EMBO Journal. 1998;17(17):5001-5014. DOI: 10.1093/emboj/17.17.5001
  49. 49. Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, et al. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Current Biology: CB. 2005;15(3):249-254. DOI: 10.1016/j.cub.2005.01.031
  50. 50. Vredeveld LC, Possik PA, Smit MA, Meissl K, Michaloglou C, Horlings HM, et al. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes & Development. 2012;26(10):1055-1069. DOI: 10.1101/gad.187252.112
  51. 51. Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181(5):1016-1035 e1019. DOI: 10.1016/j.cell.2020.04.035
  52. 52. Riffell JL, Zimmerman C, Khong A, McHardy LM, Roberge M. Effects of chemical manipulation of mitotic arrest and slippage on cancer cell survival and proliferation. Cell Cycle (Georgetown, Texas). 2009;8(18):3025-3038
  53. 53. Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J. Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene. 2014;33(1):116-128. DOI: 10.1038/onc.2013.96
  54. 54. Mosieniak G, Sliwinska MA, Alster O, Strzeszewska A, Sunderland P, Piechota M, et al. Polyploidy formation in doxorubicin-treated cancer cells can favor escape from senescence. Neoplasia (New York, NY). 2015;17(12):882-893. DOI: 10.1016/j.neo.2015.11.008
  55. 55. Erenpreisa J, Salmiņa K, Belyayev A, Inashkina I, Cragg MS. Survival at the brink. In: Hayat MA, editor. Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging. Vol. 3. 1 ed. Amsterdam, The Netherlands: Elsevier; 2017. pp. 275-294
  56. 56. Illidge TM, Cragg MS, Fringes B, Olive P, Erenpreisa JA. Polyploid giant cells provide a survival mechanism for p53 mutant cells after DNA damage. Cell Biology International. 2000;24(9):621-633. DOI: 10.1006/cbir.2000.0557
  57. 57. Shaffer SM, Dunagin MC, Torborg SR, Torre EA, Emert B, Krepler C, et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature. 2017;546(7658):431-435. DOI: 10.1038/nature22794
  58. 58. Vilgelm AE, Cobb P, Malikayil K, Flaherty D, Andrew Johnson C, Raman D, et al. MDM2 antagonists counteract drug-induced DNA damage. eBioMedicine. 2017;24:43-55. DOI: 10.1016/j.ebiom.2017.09.016
  59. 59. Leikam C, Hufnagel AL, Otto C, Murphy DJ, Mühling B, Kneitz S, et al. In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells. Cell Death & Disease. 2015;6(4):e1711. DOI: 10.1038/cddis.2015.71
  60. 60. Sagata N. What does Mos do in oocytes and somatic cells? BioEssays. 1997;19(1):13-21. DOI: 10.1002/bies.950190105
  61. 61. Tachibana K, Tanaka D, Isobe T, Kishimoto T. c-Mos forces the mitotic cell cycle to undergo meiosis II to produce haploid gametes. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(26):14301-14306. DOI: 10.1073/pnas.97.26.14301
  62. 62. Salmina K, Huna A, Kalejs M, Pjanova D, Scherthan H, Cragg MS, et al. The cancer aneuploidy paradox: In the light of evolution. Genes. 2019;10(2):83. DOI: 10.3390/genes10020083
  63. 63. Bruggen PVD, Szikora J-P, Boël P, Wildmann C, Somville M, Sensi M, et al. Autologous cytolytic T lymphocytes recognize a MAGE-1 nonapeptide on melanomas expressing HLA-Cw* 1601. European Journal of Immunology. 1994;24(9):2134-2140. DOI: 10.1002/eji.1830240930
  64. 64. Boël P, Wildmann C, Sensi ML, Brasseur R, Renauld JC, Coulie P, et al. BAGE: A new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes. Immunity. 1995;2(2):167-175. DOI: 10.1016/s1074-7613(95)80053-0
  65. 65. Chen YT, Güre AO, Tsang S, Stockert E, Jäger E, Knuth A, et al. Identification of multiple cancer/testis antigens by allogeneic antibody screening of a melanoma cell line library. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(12):6919-6923. DOI: 10.1073/pnas.95.12.6919
  66. 66. Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science (New York, N.Y.). 1991;254(5038):1643-1647. DOI: 10.1126/science.1840703
  67. 67. Van den Eynde B, Peeters O, De Backer O, Gaugler B, Lucas S, Boon T. A new family of genes coding for an antigen recognized by autologous cytolytic T lymphocytes on a human melanoma. The Journal of Experimental Medicine. 1995;182(3):689-698. DOI: 10.1084/jem.182.3.689
  68. 68. Gaugler B, Van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. The Journal of Experimental Medicine. 1994;179(3):921-930. DOI: 10.1084/jem.179.3.921
  69. 69. De Backer O, Arden KC, Boretti M, Vantomme V, De Smet C, Czekay S, et al. Characterization of the GAGE genes that are expressed in various human cancers and in normal testis. Cancer Research. 1999;59(13):3157-3165
  70. 70. Sahin U, Türeci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(25):11810-11813. DOI: 10.1073/pnas.92.25.11810
  71. 71. Almeida LG, Sakabe NJ, deOliveira AR, Silva MC, Mundstein AS, Cohen T, et al. CT database: A knowledge-base of high-throughput and curated data on cancer-testis antigens. Nucleic Acids Research. 2009;37(Database issue):D816-D819. DOI: 10.1093/nar/gkn673
  72. 72. Nelson PT, Zhang PJ, Spagnoli GC, Tomaszewski JE, Pasha TL, Frosina D, et al. Cancer/testis (CT) antigens are expressed in fetal ovary. Cancer Immunity. 2007;7:1
  73. 73. Jungbluth AA, Silva WA Jr, Iversen K, Frosina D, Zaidi B, Coplan K, et al. Expression of cancer-testis (CT) antigens in placenta. Cancer Immunity. 2007;7:15
  74. 74. Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nature Reviews Cancer. 2005;5(8):615-625. DOI: 10.1038/nrc1669
  75. 75. Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, et al. The DNA sequence of the human X chromosome. Nature. 2005;434(7031):325-337. DOI: 10.1038/nature03440
  76. 76. Chen Y-T, Iseli C, Venditti CA, Old LJ, Simpson AJG, Jongeneel CV. Identification of a new cancer/testis gene family, CT47, among expressed multicopy genes on the human X chromosome. Genes, Chromosomes & Cancer. 2006;45(4):392-400. DOI: 10.1002/gcc.20298
  77. 77. Goydos JS, Patel M, Shih W. NY-ESO-1 and CTp11 expression may correlate with stage of progression in melanoma. The Journal of Surgical Research. 2001;98(2):76-80. DOI: 10.1006/jsre.2001.6148
  78. 78. Brasseur F, Rimoldi D, Liénard D, Lethé B, Carrel S, Arienti F, et al. Expression of MAGE genes in primary and metastatic cutaneous melanoma. International Journal of Cancer. 1995;63(3):375-380. DOI: 10.1002/ijc.2910630313
  79. 79. Velazquez EF, Jungbluth AA, Yancovitz M, Gnjatic S, Adams S, O’Neill D, et al. Expression of the cancer/testis antigen NY-ESO-1 in primary and metastatic malignant melanoma (MM)—Correlation with prognostic factors. Cancer Immunity. 2007;7:11
  80. 80. Svobodová S, Browning J, MacGregor D, Pollara G, Scolyer R, Murali R, et al. Cancer–testis antigen expression in primary cutaneous melanoma has independent prognostic value comparable to that of Breslow thickness, ulceration and mitotic rate *. European Journal of Cancer (Oxford, England: 1990). 2011;47:460-469. DOI: 10.1016/j.ejca.2010.09.042
  81. 81. Badal B, Solovyov A, Di Cecilia S, Chan JM, Chang L-W, Iqbal R, et al. Transcriptional dissection of melanoma identifies a high-risk subtype underlying TP53 family genes and epigenome deregulation. JCI Insight [Internet]. 2017;2(9):e92102. DOI: 10.1172/jci.insight.92102
  82. 82. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Research. 2015;43(Database issue):D447-D452. DOI: 10.1093/nar/gku1003
  83. 83. Epping MT, Wang L, Edel MJ, Carlée L, Hernandez M, Bernards R. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 2005;122(6):835-847. DOI: 10.1016/j.cell.2005.07.003
  84. 84. Yang B, O’Herrin SM, Wu J, Reagan-Shaw S, Ma Y, Bhat KM, et al. MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Research. 2007;67(20):9954-9962. DOI: 10.1158/0008-5472.can-07-1478
  85. 85. Monte M, Simonatto M, Peche LY, Bublik DR, Gobessi S, Pierotti MA, et al. MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(30):11160-11165. DOI: 10.1073/pnas.0510834103
  86. 86. Peche LY, Scolz M, Ladelfa MF, Monte M, Schneider C. MageA2 restrains cellular senescence by targeting the function of PMLIV/p53 axis at the PML-NBs. Cell Death and Differentiation. 2012;19(6):926-936. DOI: 10.1038/cdd.2011.173
  87. 87. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature. 2000;406(6792):207-210. DOI: 10.1038/35018127
  88. 88. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: Epigenetics joins genetics. Trends in Genetics: TIG. 2000;16(4):168-174. DOI: 10.1016/s0168-9525(99)01971-x
  89. 89. Kimmins S, Sassone-Corsi P. Chromatin remodelling and epigenetic features of germ cells. Nature. 2005;434(7033):583-589. DOI: 10.1038/nature03368
  90. 90. De Smet C, Lurquin C, Lethé B, Martelange V, Boon T. DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Molecular and Cellular Biology. 1999;19(11):7327-7335. DOI: 10.1128/mcb.19.11.7327
  91. 91. Coral S, Sigalotti L, Altomonte M, Engelsberg A, Colizzi F, Cattarossi I, et al. 5-Aza-2′-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: Immunotherapeutic implications. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2002;8(8):2690-2695
  92. 92. Old LJ. Cancer/testis (CT) antigens—A new link between gametogenesis and cancer. Cancer Immunity. 2001;1:1
  93. 93. Kalejs M, Erenpreisa J. Cancer/testis antigens and gametogenesis: A review and “brain-storming” session. Cancer Cell International. 2005;5(1):4. DOI: 10.1186/1475-2867-5-4
  94. 94. Lee AK, Potts PR. A comprehensive guide to the MAGE family of ubiquitin ligases. Journal of Molecular Biology. 2017;429(8):1114-1142. DOI: 10.1016/j.jmb.2017.03.005
  95. 95. Lipkowitz S, Weissman AM. RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nature Reviews Cancer. 2011;11(9):629-643. DOI: 10.1038/nrc3120
  96. 96. Kouprina N, Mullokandov M, Rogozin IB, Collins NK, Solomon G, Otstot J, et al. The SPANX gene family of cancer/testis-specific antigens: Rapid evolution and amplification in African great apes and hominids. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(9):3077-3082. DOI: 10.1073/pnas.0308532100
  97. 97. Rajagopalan K, Mooney SM, Parekh N, Getzenberg RH, Kulkarni P. A majority of the cancer/testis antigens are intrinsically disordered proteins. Journal of Cellular Biochemistry. 2011;112(11):3256-3267. DOI: 10.1002/jcb.23252
  98. 98. Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN. Flexible nets. The roles of intrinsic disorder in protein interaction networks. The FEBS Journal. 2005;272(20):5129-5148. DOI: 10.1111/j.1742-4658.2005.04948.x
  99. 99. Radivojac P, Iakoucheva LM, Oldfield CJ, Obradovic Z, Uversky VN, Dunker AK. Intrinsic disorder and functional proteomics. Biophysical Journal. 2007;92(5):1439-1456. DOI: 10.1529/biophysj.106.094045
  100. 100. Darling AL, Uversky VN. Intrinsic disorder and posttranslational modifications: The darker side of the biological dark matter. Frontiers in Genetics. 2018;9:158. DOI: 10.3389/fgene.2018.00158
  101. 101. Giuliani A, Di Paola L. The two faces of protein flexibility: A topological approach. Current Chemical Biology. 2018;12:14. DOI: 10.2174/2212796811666170717113552
  102. 102. Tanner MM, Grenman S, Koul A, Johannsson O, Meltzer P, Pejovic T, et al. Frequent amplification of chromosomal region 20q12-q13 in ovarian cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2000;6(5):1833-1839
  103. 103. Hidaka S, Yasutake T, Takeshita H, Kondo M, Tsuji T, Nanashima A, et al. Differences in 20q13.2 copy number between colorectal cancers with and without liver metastasis. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2000;6(7):2712-2717
  104. 104. Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, Chernukhin I, et al. BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(10):6806-6811. DOI: 10.1073/pnas.092123699
  105. 105. Kholmanskikh O, Loriot A, Brasseur F, De Plaen E, De Smet C. Expression of BORIS in melanoma: Lack of association with MAGE-A1 activation. International Journal of Cancer. 2008;122(4):777-784. DOI: 10.1002/ijc.23140
  106. 106. Klenova EM, Morse HC 3rd, Ohlsson R, Lobanenkov VV. The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer. Seminars in Cancer Biology. 2002;12(5):399-414. DOI: 10.1016/s1044-579x(02)00060-3
  107. 107. Janssen SM, Moscona R, Elchebly M, Papadakis AI, Redpath M, Wang H, et al. BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cells. Cell Death Discovery. 2020;6:1. DOI: 10.1038/s41420-019-0235-x
  108. 108. Phillips JE, Corces VG. CTCF: Master weaver of the genome. Cell. 2009;137(7):1194-1211. DOI: 10.1016/j.cell.2009.06.001
  109. 109. Marshall AD, Bailey CG, Rasko JE. CTCF and BORIS in genome regulation and cancer. Current Opinion in Genetics & Development. 2014;24:8-15. DOI: 10.1016/j.gde.2013.10.011
  110. 110. Smith IM, Glazer CA, Mithani SK, Ochs MF, Sun W, Bhan S, et al. Coordinated activation of candidate proto-oncogenes and cancer testes antigens via promoter demethylation in head and neck cancer and lung cancer. PLoS One. 2009;4(3):e4961. DOI: 10.1371/journal.pone.0004961
  111. 111. Renaud S, Loukinov D, Alberti L, Vostrov A, Kwon YW, Bosman FT, et al. BORIS/CTCFL-mediated transcriptional regulation of the hTERT telomerase gene in testicular and ovarian tumor cells. Nucleic Acids Research. 2011;39(3):862-873. DOI: 10.1093/nar/gkq827
  112. 112. Liu Q , Chen K, Liu Z, Huang Y, Zhao R, Wei L, et al. BORIS up-regulates OCT4 via histone methylation to promote cancer stem cell-like properties in human liver cancer cells. Cancer Letters. 2017;403:165-174. DOI: 10.1016/j.canlet.2017.06.017
  113. 113. Zampieri M, Ciccarone F, Palermo R, Cialfi S, Passananti C, Chiaretti S, et al. The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells. Biochimica et Biophysica Acta. 2014;1839(9):813-825. DOI: 10.1016/j.bbagrm.2014.06.017
  114. 114. Nguyen P, Bar-Sela G, Sun L, Bisht KS, Cui H, Kohn E, et al. BAT3 and SET1A form a complex with CTCFL/BORIS to modulate H3K4 histone dimethylation and gene expression. Molecular and Cellular Biology. 2008;28(21):6720-6729. DOI: 10.1128/mcb.00568-08
  115. 115. Sun L, Huang L, Nguyen P, Bisht KS, Bar-Sela G, Ho AS, et al. DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation. Cancer Research. 2008;68(8):2726-2735. DOI: 10.1158/0008-5472.can-07-6654
  116. 116. Kosaka-Suzuki N, Suzuki T, Pugacheva EM, Vostrov AA, Morse HC 3rd, Loukinov D, et al. Transcription factor BORIS (Brother of the Regulator of Imprinted Sites) directly induces expression of a cancer-testis antigen, TSP50, through regulated binding of BORIS to the promoter. The Journal of Biological Chemistry. 2011;286(31):27378-27388. DOI: 10.1074/jbc.M111.243576
  117. 117. Vatolin S, Abdullaev Z, Pack SD, Flanagan PT, Custer M, Loukinov DI, et al. Conditional expression of the CTCF-paralogous transcriptional factor BORIS in normal cells results in demethylation and derepression of MAGE-A1 and reactivation of other cancer-testis genes. Cancer Research. 2005;65(17):7751-7762. DOI: 10.1158/0008-5472.can-05-0858
  118. 118. Hillman J, Pugacheva E, Barger C, Sribenja S, Rosario S, Albahrani M, et al. BORIS expression in ovarian cancer precursor cells alters the CTCF cistrome and enhances invasiveness through GALNT14. Molecular Cancer Research. 2019;17(10):2051-2062. DOI: 10.1158/1541-7786.MCR-19-0310
  119. 119. Alberti L, Losi L, Leyvraz S, Benhattar J. Different effects of BORIS/CTCFL on stemness gene expression, sphere formation and cell survival in epithelial cancer stem cells. PLoS One. 2015;10(7):e0132977. DOI: 10.1371/journal.pone.0132977
  120. 120. Alberti L, Renaud S, Losi L, Leyvraz S, Benhattar J. High expression of hTERT and stemness genes in BORIS/CTCFL positive cells isolated from embryonic cancer cells. PLoS One. 2014;9(10):e109921. DOI: 10.1371/journal.pone.0109921
  121. 121. Link PA, Zhang W, Odunsi K, Karpf AR. BORIS/CTCFL mRNA isoform expression and epigenetic regulation in epithelial ovarian cancer. Cancer Immunity. 2013;13:6
  122. 122. Murakami S, Ninomiya W, Sakamoto E, Shibata T, Akiyama H, Tashiro F. SRY and OCT4 are required for the acquisition of cancer stem cell-like properties and are potential differentiation therapy targets. Stem Cells (Dayton, Ohio). 2015;33(9):2652-2663. DOI: 10.1002/stem.2059
  123. 123. Kumar SM, Liu S, Lu H, Zhang H, Zhang PJ, Gimotty PA, et al. Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene. 2012;31(47):4898-4911. DOI: 10.1038/onc.2011.656
  124. 124. Wang YJ, Herlyn M. The emerging roles of Oct4 in tumor-initiating cells. American Journal of Physiology-Cell Physiology. 2015;309(11):C709-C718. DOI: 10.1152/ajpcell.00212.2015
  125. 125. Zhao W, Li Y, Zhang X. Stemness-related markers in cancer. Cancer Translational Medicine. 2017;3(3):87-95. DOI: 10.4103/ctm.ctm_69_16
  126. 126. Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, et al. TCGAbiolinks: An R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Research. 2016;44(8):e71. DOI: 10.1093/nar/gkv1507
  127. 127. Robinson MD, McCarthy DJ, Smyth GK. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics (Oxford, England). 2010;26(1):139-140. DOI: 10.1093/bioinformatics/btp616
  128. 128. Waskom MB, Olga O, Kane HD, Lukauskas P, Gemperline S, et al. Seaborn. v0.8. 1st ed. Internet. Meyrin, Switzerland: Zenodo; 2017
  129. 129. Boregowda RK, Medina DJ, Markert E, Bryan MA, Chen W, Chen S, et al. The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma. Oncotarget. 2016;7(20):29689-29707. DOI: 10.18632/oncotarget.8822
  130. 130. Sinnberg T, Levesque MP, Krochmann J, Cheng PF, Ikenberg K, Meraz-Torres F, et al. Wnt-signaling enhances neural crest migration of melanoma cells and induces an invasive phenotype. Molecular Cancer. 2018;17(1):59. DOI: 10.1186/s12943-018-0773-5
  131. 131. McFarlane RJ, Wakeman JA. Meiosis-like functions in oncogenesis: A new view of cancer. Cancer Research. 2017;77(21):5712-5716. DOI: 10.1158/0008-5472.can-17-1535
  132. 132. Keeney S, Giroux CN, Kleckner N. Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell. 1997;88(3):375-384. DOI: 10.1016/s0092-8674(00)81876-0
  133. 133. Baudat F, Manova K, Yuen JP, Jasin M, Keeney S. Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Molecular Cell. 2000;6(5):989-998. DOI: 10.1016/s1097-2765(00)00098-8
  134. 134. Romanienko PJ, Camerini-Otero RD. The mouse Spo11 gene is required for meiotic chromosome synapsis. Molecular Cell. 2000;6(5):975-987. DOI: 10.1016/s1097-2765(00)00097-6
  135. 135. Koslowski M, Türeci O, Bell C, Krause P, Lehr HA, Brunner J, et al. Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer. Cancer Research. 2002;62(22):6750-6755
  136. 136. Atanackovic D, Luetkens T, Kloth B, Fuchs G, Cao Y, Hildebrandt Y, et al. Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. American Journal of Hematology. 2011;86(11):918-922. DOI: 10.1002/ajh.22141
  137. 137. Litvinov IV, Cordeiro B, Huang Y, Zargham H, Pehr K, Doré MA, et al. Ectopic expression of cancer-testis antigens in cutaneous T-cell lymphoma patients. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2014;20(14):3799-3808. DOI: 10.1158/1078-0432.ccr-14-0307
  138. 138. Eldai H, Periyasamy S, Al Qarni S, Al Rodayyan M, Muhammed Mustafa S, Deeb A, et al. Novel genes associated with colorectal cancer are revealed by high resolution cytogenetic analysis in a patient specific manner. PLoS One. 2013;8(10):e76251. DOI: 10.1371/journal.pone.0076251
  139. 139. Tsang M, Gantchev J, Netchiporouk E, Moreau L, Ghazawi FM, Glassman S, et al. A study of meiomitosis and novel pathways of genomic instability in cutaneous T-cell lymphomas (CTCL). Oncotarget. 2018;9(102):37647-37661. DOI: 10.18632/oncotarget.26479
  140. 140. Kim S, Peterson SE, Jasin M, Keeney S. Mechanisms of germ line genome instability. Seminars in Cell & Developmental Biology. 2016;54:177-187. DOI: 10.1016/j.semcdb.2016.02.019
  141. 141. Nagirnaja L, Aston KI, Conrad DF. Genetic intersection of male infertility and cancer. Fertility and Sterility. 2018;109(1):20-26. DOI: 10.1016/j.fertnstert.2017.10.028
  142. 142. Dernburg AF, McDonald K, Moulder G, Barstead R, Dresser M, Villeneuve AM. Meiotic recombination in C. elegans initiates by a conserved mechanism and is dispensable for homologous chromosome synapsis. Cell. 1998;94(3):387-398. DOI: 10.1016/s0092-8674(00)81481-6
  143. 143. Keeney S. Spo11 and the formation of DNA double-strand breaks in meiosis. Genome Dynamics and Stability. 2008;2:81-123. DOI: 10.1007/7050_2007_026
  144. 144. Klein U, Esposito G, Baudat F, Keeney S, Jasin M. Mice deficient for the type II topoisomerase-like DNA transesterase Spo11 show normal immunoglobulin somatic hypermutation and class switching. European Journal of Immunology. 2002;32(2):316-321. DOI: 10.1002/1521-4141(200202)32:2<316::aid-immu316>3.0.co;2-p
  145. 145. Prieler S, Penkner A, Borde V, Klein F. The control of Spo11’s interaction with meiotic recombination hotspots. Genes & Development. 2005;19(2):255-269. DOI: 10.1101/gad.321105
  146. 146. Huna A, Salmina K, Erenpreisa J, Vazquez-Martin A, Krigerts J, Inashkina I, et al. Role of stress-activated OCT4A in the cell fate decisions of embryonal carcinoma cells treated with etoposide. Cell Cycle (Georgetown, Texas). 2015;14(18):2969-2984. DOI: 10.1080/15384101.2015.1056948
  147. 147. Tock AJ, Henderson IR. Hotspots for initiation of meiotic recombination. Frontiers in Genetics. 2018;9:521. DOI: 10.3389/fgene.2018.00521
  148. 148. Neale MJ, Pan J, Keeney S. Endonucleolytic processing of covalent protein-linked DNA double-strand breaks. Nature. 2005;436(7053):1053-1057. DOI: 10.1038/nature03872
  149. 149. Bomblies K, Higgins JD, Yant L. Meiosis evolves: Adaptation to external and internal environments. New Phytologist. 2015;208(2):306-323. DOI: 10.1111/nph.13499
  150. 150. Yant L, Bomblies K. Genome management and mismanagement--cell-level opportunities and challenges of whole-genome duplication. Genes & Development. 2015;29(23):2405-2419. DOI: 10.1101/gad.271072.115
  151. 151. Feichtinger J, Aldeailej I, Anderson R, Almutairi M, Almatrafi A, Alsiwiehri N, et al. Meta-analysis of clinical data using human meiotic genes identifies a novel cohort of highly restricted cancer-specific marker genes. Oncotarget. 2012;3(8):843-853. DOI: 10.18632/oncotarget.580
  152. 152. Loriot A, Boon T, De Smet C. Five new human cancer-germline genes identified among 12 genes expressed in spermatogonia. International Journal of Cancer. 2003;105(3):371-376. DOI: 10.1002/ijc.11104
  153. 153. Liu JG, Yuan L, Brundell E, Björkroth B, Daneholt B, Höög C. Localization of the N-terminus of SCP1 to the central element of the synaptonemal complex and evidence for direct interactions between the N-termini of SCP1 molecules organized head-to-head. Experimental Cell Research. 1996;226(1):11-19. DOI: 10.1006/excr.1996.0197
  154. 154. Schmekel K, Meuwissen RL, Dietrich AJ, Vink AC, van Marle J, van Veen H, et al. Organization of SCP1 protein molecules within synaptonemal complexes of the rat. Experimental Cell Research. 1996;226(1):20-30. DOI: 10.1006/excr.1996.0198
  155. 155. Ollinger R, Alsheimer M, Benavente R. Mammalian protein SCP1 forms synaptonemal complex-like structures in the absence of meiotic chromosomes. Molecular Biology of the Cell. 2005;16(1):212-217. DOI: 10.1091/mbc.e04-09-0771
  156. 156. Costa Y, Speed R, Ollinger R, Alsheimer M, Semple CA, Gautier P, et al. Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the Centre of meiosis. Journal of Cell Science 2005; 118 (Pt 12):2755-2762. doi:10.1242/jcs.02402
  157. 157. Türeci O, Sahin U, Zwick C, Koslowski M, Seitz G, Pfreundschuh M. Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(9):5211-5216. DOI: 10.1073/pnas.95.9.5211
  158. 158. Mobasheri MB, Jahanzad I, Mohagheghi MA, Aarabi M, Farzan S, Modarressi MH. Expression of two testis-specific genes, TSGA10 and SYCP3, in different cancers regarding to their pathological features. Cancer Detection and Prevention. 2007;31(4):296-302. DOI: 10.1016/j.cdp.2007.05.002
  159. 159. Cho H, Noh KH, Chung JY, Takikita M, Chung EJ, Kim BW, et al. Synaptonemal complex protein 3 is a prognostic marker in cervical cancer. PLoS One. 2014;9(6):e98712. DOI: 10.1371/journal.pone.0098712
  160. 160. Chung JY, Kitano H, Takikita M, Cho H, Noh KH, Kim TW, et al. Synaptonemal complex protein 3 as a novel prognostic marker in early stage non-small cell lung cancer. Human Pathology. 2013;44(4):472-479. DOI: 10.1016/j.humpath.2012.06.018
  161. 161. Daniel K, Lange J, Hached K, Fu J, Anastassiadis K, Roig I, et al. Meiotic homologue alignment and its quality surveillance are controlled by mouse HORMAD1. Nature Cell Biology. 2011;13(5):599-610. DOI: 10.1038/ncb2213
  162. 162. Yao J, Caballero OL, Yung WK, Weinstein JN, Riggins GJ, Strausberg RL, et al. Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers. Cancer Immunology Research. 2014;2(4):371-379. DOI: 10.1158/2326-6066.cir-13-0088
  163. 163. Nichols BA, Oswald NW, McMillan EA, McGlynn K, Yan J, Kim MS, et al. HORMAD1 is a negative prognostic indicator in lung adenocarcinoma and specifies resistance to oxidative and genotoxic stress. Cancer Research. 2018;78(21):6196-6208. DOI: 10.1158/0008-5472.can-18-1377
  164. 164. Wang X, Tan Y, Cao X, Kim JA, Chen T, Hu Y, et al. Epigenetic activation of HORMAD1 in basal-like breast cancer: Role in rucaparib sensitivity. Oncotarget. 2018;9(53):30115-30127. DOI: 10.18632/oncotarget.25728
  165. 165. Ishiguro KI. The cohesin complex in mammalian meiosis. Genes to Cells: Devoted to Molecular & Cellular Mechanisms. 2019;24(1):6-30. DOI: 10.1111/gtc.12652
  166. 166. Rosa AM, Dabas N, Byrnes DM, Eller MS, Grichnik JM. Germ cell proteins in melanoma: Prognosis, diagnosis, treatment, and theories on expression. Journal of Skin Cancer. 2012;2012:621968. DOI: 10.1155/2012/621968
  167. 167. Gantchev J, Martínez Villarreal A, Xie P, Lefrançois P, Gunn S, Netchiporouk E, et al. The ectopic expression of meiosis regulatory genes in cutaneous T-cell lymphomas (CTCL). Frontiers in Oncology. 2019;9:429. DOI: 10.3389/fonc.2019.00429
  168. 168. Erenpreisa J, Cragg MS, Salmina K, Hausmann M, Scherthan H. The role of meiotic cohesin REC8 in chromosome segregation in gamma irradiation-induced endopolyploid tumour cells. Experimental Cell Research. 2009;315(15):2593-2603. DOI: 10.1016/j.yexcr.2009.05.011
  169. 169. Folco HD, Chalamcharla VR, Sugiyama T, Thillainadesan G, Zofall M, Balachandran V, et al. Untimely expression of gametogenic genes in vegetative cells causes uniparental disomy. Nature. 2017;543(7643):126-130. DOI: 10.1038/nature21372
  170. 170. Wolf PG, Cuba Ramos A, Kenzel J, Neumann B, Stemmann O. Studying meiotic cohesin in somatic cells reveals that Rec8-containing cohesin requires Stag3 to function and is regulated by Wapl and sororin. Journal of Cell Science. 2018;131(11):jcs212100. DOI: 10.1242/jcs.212100
  171. 171. Shen CH, Kim SH, Trousil S, Frederick DT, Piris A, Yuan P, et al. Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nature Medicine. 2016;22(9):1056-1061. DOI: 10.1038/nm.4155
  172. 172. Brar GA, Amon A. Emerging roles for centromeres in meiosis I chromosome segregation. Nature Reviews Genetics. 2008;9(12):899-910. DOI: 10.1038/nrg2454
  173. 173. Eijpe M, Offenberg H, Jessberger R, Revenkova E, Heyting C. Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1beta and SMC3. The Journal of Cell Biology. 2003;160(5):657-670. DOI: 10.1083/jcb.200212080
  174. 174. Kitajima TS, Sakuno T, Ishiguro K, Iemura S, Natsume T, Kawashima SA, et al. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature. 2006;441(7089):46-52. DOI: 10.1038/nature04663
  175. 175. Herrán Y, Gutiérrez-Caballero C, Sanchez-Martin M, Hernández T, Viera A, Barbero J, et al. The cohesin subunit RAD21L functions in meiotic synapsis and exhibits sexual dimorphism in fertility. The EMBO Journal. 2011;30:3091-3105. DOI: 10.1038/emboj.2011.222
  176. 176. De Vitis M, Berardinelli F, Sgura A. Telomere length maintenance in cancer: At the crossroad between telomerase and alternative lengthening of telomeres (ALT). International Journal of Molecular Sciences. 2018;19(2):606. DOI: 10.3390/ijms19020606
  177. 177. Salmina K, Bojko A, Inashkina I, Staniak K, Dudkowska M, Podlesniy P, et al. “mitotic slippage” and extranuclear DNA in cancer chemoresistance: A focus on telomeres. International Journal of Molecular Sciences. 2020;21(8):2779. DOI: 10.3390/ijms21082779
  178. 178. Cho NW, Dilley RL, Lampson MA, Greenberg RA. Interchromosomal homology searches drive directional ALT telomere movement and synapsis. Cell. 2014;159(1):108-121. DOI: 10.1016/j.cell.2014.08.030
  179. 179. Rong M, Miyauchi S, Lee J. Ectopic expression of meiotic cohesin RAD21L promotes adjacency of homologous chromosomes in somatic cells. The Journal of Reproduction and Development. 2017;63(3):227-234. DOI: 10.1262/jrd.2016-171
  180. 180. Dilley RL, Verma P, Cho NW, Winters HD, Wondisford AR, Greenberg RA. Break-induced telomere synthesis underlies alternative telomere maintenance. Nature. 2016;539(7627):54-58. DOI: 10.1038/nature20099
  181. 181. Dobzhansky T. Nothing in biology makes sense except in the light of evolution. The American Biology Teacher. 1973;35(3):125-129. DOI: 10.2307/4444260
  182. 182. Weinberg RA. Coming full circle-from endless complexity to simplicity and back again. Cell. 2014;157(1):267-271. DOI: 10.1016/j.cell.2014.03.004
  183. 183. Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nature Cell Biology. 2019;21(1):94-101. DOI: 10.1038/s41556-018-0249-2
  184. 184. Grichnik JM. Genomic instability and tumor stem cells. The Journal of Investigative Dermatology. 2006;126(6):1214-1216. DOI: 10.1038/sj.jid.5700240
  185. 185. Grichnik JM. Melanoma, nevogenesis, and stem cell biology. The Journal of Investigative Dermatology. 2008;128(10):2365-2380. DOI: 10.1038/jid.2008.166
  186. 186. Sheltzer JM, Amon A. The aneuploidy paradox: Costs and benefits of an incorrect karyotype. Trends in Genetics: TIG. 2011;27(11):446-453. DOI: 10.1016/j.tig.2011.07.003
  187. 187. Muller HJ. The relation of recombination to mutational advance. Mutation Research. 1964;106:2-9. DOI: 10.1016/0027-5107(64)90047-8
  188. 188. Neher RA, Shraiman BI. Fluctuations of fitness distributions and the rate of Muller’s ratchet. Genetics. 2012;191(4):1283-1293. DOI: 10.1534/genetics.112.141325
  189. 189. Amend SR, Torga G, Lin KC, Kostecka LG, de Marzo A, Austin RH, et al. Polyploid giant cancer cells: Unrecognized actuators of tumorigenesis, metastasis, and resistance. The Prostate. 2019;79(13):1489-1497. DOI: 10.1002/pros.23877
  190. 190. Coward J, Harding A. Size does matter: Why polyploid tumor cells are critical drug targets in the war on cancer. Frontiers in Oncology. 2014;4:123. DOI: 10.3389/fonc.2014.00123
  191. 191. Mirzayans R, Andrais B, Murray D. Roles of polyploid/multinucleated giant cancer cells in metastasis and disease relapse following anticancer treatment. Cancers. 2018;10(4):118. DOI: 10.3390/cancers10040118
  192. 192. Chen J, Niu N, Zhang J, Qi L, Shen W, Donkena KV, et al. Polyploid giant cancer cells (PGCCs): The evil roots of cancer. Current Cancer Drug Targets. 2019;19(5):360-367. DOI: 10.2174/1568009618666180703154233
  193. 193. Erenpreisa J, Cragg M. Cancer: A matter of life cycle? Cell Biology International. 2007;31:1507-1510. DOI: 10.1016/j.cellbi.2007.08.013
  194. 194. Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R. Neosis: A novel type of cell division in cancer. Cancer Biology & Therapy. 2004;3(2):207-218. DOI: 10.4161/cbt.3.2.663
  195. 195. Rajaraman R, Guernsey D, Rajaraman M, Rajaraman S. Neosis—A parasexual somatic reduction division in cancer. International Journal of Human Genetics. 2007;7:29-48. DOI: 10.1080/09723757.2007.11885983
  196. 196. Salmina K, Jankevics E, Huna A, Perminov D, Radovica I, Klymenko T, et al. Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells. Experimental Cell Research. 2010;316(13):2099-2112. DOI: 10.1016/j.yexcr.2010.04.030
  197. 197. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells (Dayton, Ohio). 2012;30(5):833-844. DOI: 10.1002/stem.1058
  198. 198. Mosieniak G, Sikora E. Polyploidy: The link between senescence and cancer. Current Pharmaceutical Design. 2010;16(6):734-740. DOI: 10.2174/138161210790883714
  199. 199. Weihua Z, Lin Q , Ramoth AJ, Fan D, Fidler IJ. Formation of solid tumors by a single multinucleated cancer cell. Cancer. 2011;117(17):4092-4099. DOI: 10.1002/cncr.26021
  200. 200. Mirzayans R, Andrais B, Murray D. Viability assessment following anticancer treatment requires single-cell visualization. Cancers. 2018;10(8):255. DOI: 10.3390/cancers10080255
  201. 201. Erenpreisa J, Cragg M, Fringes B, Sharakhov I. Release of mitotic descendents by giant cells from Burkitt's lymphoma cell line. Cell Biology International. 2000;24:635-648. DOI: 10.1006/cbir.2000.0558
  202. 202. Erenpreisa J, Kalejs M, Ianzini F, Kosmacek EA, Mackey MA, Emzinsh D, et al. Segregation of genomes in polyploid tumour cells following mitotic catastrophe. Cell Biology International. 2005;29(12):1005-1011. DOI: 10.1016/j.cellbi.2005.10.008
  203. 203. Comai L. The advantages and disadvantages of being polyploid. Nature Reviews Genetics. 2005;6(11):836-846. DOI: 10.1038/nrg1711
  204. 204. Markov AV, Kaznacheev IS. Evolutionary consequences of polyploidy in prokaryotes and the origin of mitosis and meiosis. Biology Direct. 2016;11:28. DOI: 10.1186/s13062-016-0131-8
  205. 205. Bernstein H, Byerly HC, Hopf FA, Michod R. DNA Repair and complementation: The major factors in the origin and maintenance of sex. In: Halvorson HO, Monroy A, editors. The Origin and Evolution of Sex. New York: Alan R.Liss Inc.; 1985. pp. 29-45
  206. 206. Kondrashov AS. The asexual ploidy cycle and the origin of sex. Nature. 1994;370(6486):213-216. DOI: 10.1038/370213a0
  207. 207. Erenpreisa J, Kalejs M, Cragg MS. Mitotic catastrophe and endomitosis in tumour cells: An evolutionary key to a molecular solution. Cell Biology International. 2005;29(12):1012-1018. DOI: 10.1016/j.cellbi.2005.10.005
  208. 208. Cleveland LR. The origin and evolution of meiosis. Science (New York, N.Y.). 1947;105(2724):287-289. DOI: 10.1126/science.105.2724.287
  209. 209. Solari AJ. Primitive forms of meiosis: The possible evolution of meiosis. Biocell. 2002;26(1):1-13
  210. 210. Loidl J. Conservation and variability of meiosis across the eukaryotes. Annual Review of Genetics. 2016;50:293-316. DOI: 10.1146/annurev-genet-120215-035100
  211. 211. Bogdanov Y. Variation and evolution of meiosis. Russian Journal of Genetics. 2003;39:363-381
  212. 212. Old LJ. Cancer is a somatic cell pregnancy. Cancer Immunity. 2007;7:19
  213. 213. Erenpreisa J, Salmina K, Huna A, Jackson TR, Vazquez-Martin A, Cragg MS. The “virgin birth”, polyploidy, and the origin of cancer. Oncoscience. 2015;2(1):3-14. DOI: 10.18632/oncoscience.108
  214. 214. Liu J. The “life code”: A theory that unifies the human life cycle and the origin of human tumors. Seminars in Cancer Biology. 2020;60:380-397. DOI: 10.1016/j.semcancer.2019.09.005
  215. 215. Vainshelbaum NM, Zayakin P, Kleina R, Giuliani A, Erenpreisa J. Meta-analysis of cancer triploidy: Rearrangements of genome complements in male human tumors are characterized by XXY karyotypes. Genes. 2019;10(8):613. DOI: 10.3390/genes10080613
  216. 216. Salmina K, Gerashchenko B, Hausmann VN, Zayakin E, et al. When three isn't a crowd: A digyny concept for treatment-resistant, near-triploid human cancers. Genes. 2019;10:551. DOI: 10.3390/genes10070551
  217. 217. Huskins CL, Cheng KC. Segregation and reduction in somatic tissues: IV. Reductional groupings induced in Allium cepa by low temperature. Journal of Heredity. 1950;41(1):13-18. DOI: 10.1093/oxfordjournals.jhered.a106043
  218. 218. Walen K. Neoplastic-like cell changes of normal fibroblast cells associated with evolutionary conserved maternal and paternal genomic autonomous behavior (Gonomery). Journal of Cancer Therapy. 2014;05:860-877. DOI: 10.4236/jct.2014.59094
  219. 219. Trigos AS, Pearson RB, Papenfuss AT, Goode DL. Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(24):6406-6411. DOI: 10.1073/pnas.1617743114
  220. 220. Erenpreisa J, Giuliani A, Vinogradov A, Anatskaya O, Vazquez-Martin A, Salmina K, et al. Stress-induced polyploidy shifts somatic cells towards a pro-tumourogenic unicellular gene transcription network hypothesis: Polyploidy enables access to transcriptional networks of unicellular organisms, which in the absence of tumour suppressors provides immortality and resistance from treatment for cancer cells. Cancer Hypotheses. 2018;1:1-20
  221. 221. Heckmann S, Jankowska M, Schubert V, Kumke K, Ma W, Houben A. Alternative meiotic chromatid segregation in the holocentric plant Luzula elegans. Nature Communications. 2014;5(1):4979. DOI: 10.1038/ncomms5979
  222. 222. Ottolini CS, Newnham L, Capalbo A, Natesan SA, Joshi HA, Cimadomo D, et al. Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates. Nature Genetics. 2015;47(7):727-735. DOI: 10.1038/ng.3306
  223. 223. Domazet-Lošo T, Klimovich A, Anokhin B, Anton-Erxleben F, Hamm MJ, Lange C, et al. Naturally occurring tumours in the basal metazoan Hydra. Nature Communications [Internet]. 2014;5:4222. DOI: 10.1038/ncomms5222
  224. 224. Erenpreisa J, Giuliani A. Resolution of complex issues in genome regulation and cancer requires non-linear and network-based thermodynamics. International Journal of Molecular Sciences. 2019;21(1):240. DOI: 10.3390/ijms21010240
  225. 225. Huang S, Ernberg I, Kauffman S. Cancer attractors: A systems view of tumors from a gene network dynamics and developmental perspective. Seminars in Cell & Developmental Biology. 2009;20(7):869-876. DOI: 10.1016/j.semcdb.2009.07.003
  226. 226. Huang S, Eichler G, Bar-Yam Y, Ingber DE. Cell fates as high-dimensional attractor states of a complex gene regulatory network. Physical Review Letters. 2005;94(12):128701. DOI: 10.1103/PhysRevLett.94.128701
  227. 227. López S, Lim EL, Horswell S. et al. Polyploidy in cancer produces the buffering effect decreasing the homozygous loss. Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution. Nature Genetics. 2020;52:283-293. Available from: http://sci-hub.tw/10.1038/s41588-020-0584-7
  228. 228. Hu T, Kumar Y, Shazia I, Duan S-J, Li Y, Chen L, et al. Forward and reverse mutations in stages of cancer development. Human Genomics. 2018;12(1):40. DOI: 10.1186/s40246-018-0170-6
  229. 229. Maciver SK. Asexual amoebae escape Muller’s ratchet through polyploidy. Trends in Parasitology. 2016;32(11):855-862. DOI: 10.1016/j.pt.2016.08.006
  230. 230. Chen JM, Férec C, Cooper DN. Gene conversion in human genetic disease. Genes. 2010;1(3):550-563. DOI: 10.3390/genes1030550

Written By

Dace Pjanova, Ninel M. Vainshelbaum, Kristine Salmina and Jekaterina Erenpreisa

Submitted: 12 May 2020 Reviewed: 19 August 2020 Published: 30 September 2020