**4. Loss of imprinting (LI) and de-repression of cancer-germline (CG) genes**

The loss of the imprinting process is largely due to DNA hypomethylation. Repression of endogenous retroviral sequences and activation of GC genes can promote malignant transformation by increasing proliferation, genomic instability, and resistance to apoptosis [63, 64].

A fascinating phenomenon can occur during the malignant transformation of somatic cells. The development of highly limited tumor antigens that induce serological and cell-mediated immune responses in cancer patients can be caused by abnormal activation of GC genes [also known as testicular cancer (TC) genes]. As a result, testicular cancer antigens (ATCs) have become popular targets for cancer immunotherapy in recent years [65]. More than 270 GC genes have been registered in the international TC database thus far. Seventy-five percent of these genes are only expressed in normal testes and malignant neoplasms, while the rest have high levels of expression in testes and varying levels of expression in other normal tissues and malignancies. On the X chromosome, around half of the GC genes are encoded. Families of cancer-testis-X (CT-X) chromosomal genes with inverted DNA repeats are common. On the other hand, inverted repetitive DNA sequences or extended families or are not linked to non-X CT genes [66, 67]. Furthermore, CT-X genes are frequently active in malignancies, and genes from families are increased in a tumorspecific manner, implying that the CT-X genes have a transcriptional coregulation and functional link.

In human malignancies, the stage at which the disease is discovered at a specific time corresponds to the degree of CG gene repression. Malignant and aggressive phenotype of cancer cells is promoted activations of this genes. BORIS/CTCFL, for example, upregulates h-TERT and suppresses apoptosis in cancer cells via processes that are still unknown [68, 69]. MAGE-A11 regulates the activity of the tumor suppressor gene RBL1/p107 [63]. MAGE-A11 inhibits the tumor suppressor gene RBL1/ p107, while MAGE-B2 promotes cell cycle advancement by increasing E2F activity. MAGE-A2 and MAGE-C2 prevent p53 from binding to target promoters, changing its activities and leading to p53 deacetylation (inactivation) or enhanced ubiquitinmediated degradation. The absence of CG gene regulation does not appear to be just a symptom of pluripotency, as it is accompanied with chromosomal hypomethylation. In human ESC, mesenchymal stem cells, and adipose-derived stem cells, Loriot et al. [70] found no overexpression of 18 different CG genes. In induced pluripotent stem cells (iPSCs) produced from normal small airway epithelial cells, transcriptional repression of CG genes such as NY-ESO-1, MAGE-A1, and MAGE-A3, which are generally located upward in thoracic malignant tumors, has been detected, which is consistent with these findings. Although these findings imply that iPSC reprogramming is partial, induction of CG genes in cancer cells may necessitate more extensive DNA hypomethylation as well as activation of tissue-specific transcription factors.

There is currently such little information on the expression of CG genes in MPM. MAGE1--4, NY-ESO-1, GAGE1-2, GAGE1-6, SSX2, SSX1-6, and RAGE-1 expression in five MPM lines was compared to normal mesothelial cells employing RT-PCR techniques, according to Sigalotti et al. [71]. In these MPM lines, diverse expressions of the CG gene were identified, with each line exhibiting a unique profile, as previously reported for lung malignancies [72]. None of these genes were found in normal mesothelial cells [71, 73].
