Ectopic Expression of Testis Germ Cell Proteins in Cancer and Its Potential Role in Genomic Instability

Abstract

Genomic instability is a hallmark of human cancer and an enabling factor for the genetic alterations that drive cancer development. The processes involved in genomic instability resemble those of meiosis, where genetic material is interchanged between homologous chromosomes. In most types of human cancer, epigenetic changes, including hypomethylation of gene promoters, lead to the ectopic expression of a large number of proteins normally restricted to the germ cells of the testis. Due to the similarities between meiosis and genomic instability, it has been proposed that activation of meiotic programs may drive genomic instability in cancer cells. Some germ cell proteins with ectopic expression in cancer cells indeed seem to promote genomic instability, while others reduce polyploidy and maintain mitotic fidelity. Furthermore, oncogenic germ cell proteins may indirectly contribute to genomic instability through induction of replication stress, similar to classic oncogenes. Thus, current evidence suggests that testis germ cell proteins are implicated in cancer development by regulating genomic instability during tumorigenesis, and these proteins therefore represent promising targets for novel therapeutic strategies.

Massive expression of germ cell specific genes is a hallmark of cancer and a potential target for novel treatment development

“…Six biological processes appeared to be significantly represented by these 189 GC-genes, including cell cycle regulation and checkpoints, post-translational protein modification and DNA damage responses (supplementary data 3G). In line with previous research 14,16,17 , these processes suggests that GC-genes are not just randomly expressed germ cell specific genes but may actually contribute to tumor cell survival, proliferation and metastasis.…”

Meiosis-like Functions in Oncogenesis: A New View of Cancer

“…These chromosomal segregation events differ considerably to those of the first meiotic division during gametogenesis, where homologous chromosomes of a diploid germline progenitor cell conjoin via programmed genetic recombination intermediates to form a bivalent, which is ultimately resolved, culminating in a reductional chromosome segregation event and "shuffled" genetic material (2,3). There is now solid emerging evidence to support the concept that the inappropriate activation of meiotic chromosome regulator genes in mitotically dividing somatic cells results in deviations in mechanisms controlling chromosome maintenance and segregation (4)(5)(6)(7)(8)(9).…”

A pseudo-meiotic centrosomal function of TEX12 in cancer

“…This likely represents a role of TEX12 that is favoured when it cannot participate in SC assembly, which may be analogous to the formation of chromatin-free SYCP1 polycomplexes in the absence of an SC in meiotic and somatic cells 32,33 . We therefore propose that, in keeping with the mechanism of other meiosis-specific genes in cancer 3,4 , the centrosomal role of TEX12 in cancer cells may represent a previously overlooked pseudomeiotic function.…”

“…Cell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes 1,2 . The many meiosisspecific genes involved in these processes also constitute a latent toolbox of chromosome remodelling and recombination factors that may be exploited through aberrant expression in cancer 3,4 . Here, we report that TEX12, a structural protein involved in meiotic chromosome synapsis [5][6][7] , is aberrantly expressed in human cancers, with high TEX12 levels correlating with poor prognosis.…”