**8. Conclusions**

While malignant pleural mesothelioma is a disease with a low incidence worldwide, with aggressive behavior, its survival does not go beyond 12 months once the diagnosis is made [1, 2]. Its origin has been related to the chronic exposure of asbestos as the main factor. Also, asbestos fibers have been an essential component in structural changes at the molecular level, with much evidence about its genetic behavior and to a lesser extent, its epigenetic behavior. All of this gives it a fairly heterogeneous behavior [13–15]. New molecular techniques allow a broader understanding of the carcinogenesis of this tumor and an approach to new diagnostic tools. Epigenetic dysregulations require active maintenance and are potentially reversible, making them a therapeutic target [7, 23, 30].

The study of methylome has made it possible to carry out differential diagnoses thanks to the methylation of some specific loci, such as TMEM30B, KAZAZD1, MAPK13 and to demonstrate greater survival rates in patients with low frequencies of methylations [16, 17, 28].

It is important to mention the exposure to asbestos fibers as the main resistance factor associated with the methylation of tumor suppressor genes seen in pleural mesothelial cells such as APC and RASSF1. Additionally, there are direct cellular effects such as chronic inflammation measured by free radicals leading to DNA oxidation, hemolysis with the release of hydroxyl ions, intrachain breakdown plus subsequent chromosomal fragmentation, and production of pro-inflammatory cytokines with higher expression of angiogenic growth factors, another aspect that can be considered a potential therapeutic objective. Genomic responses related to methylation conclude in a gene silencing, most likely in tumor suppressor genes such as SFRP4, FHIT, SLCA20 [69, 71, 80]. Another diagnostic approach that can be observed by methylation is the overexpression of DNMT in patients with MPM and consequently could be an attractive therapeutic target, however, clinical efforts for its inhibition have been disappointing and future studies should focus on the therapeutic approach to the inhibition of DNMT.

A greater association of methylation has been seen in advanced ages and ethnic groups such as the Japanese population. However, the greater association related to histological changes in proliferation, differentiation, invasion, and reduction of apoptosis has been seen with the increased methylation of CpG islands in genes such as CCND2, CDKN2A, and associated with asbestos bodies with RASSF1.

Although methylation is the most studied epigenetic mechanism, there are other modifications that lead to the silencing of tumor suppressor genes, such as the activation of the Polycomb complex and the mutation of the SWI/SNF pathway [82, 83]. Deacetylation mediated by HDAC has been seen in the p53 gene and other aspects such as HAT-mediated acetylation or demethylation by KDMs.

The modification in histone features such as stability in chromatin has a great relationship with HDCAs, thus making them a potential therapeutic target. There are few studies with inhibitors such as vorinostat, however, where there are no positive results due to the low expression in MPM.

Finally, it is clear that there is much to know about the modifications and/or epigenetic changes in MPM. The current evidence of the molecular mechanisms opens up another panorama for us to adjust personalized therapeutic strategies aimed at reversing normal changes and thus be able to identify in a timely manner those patients who are susceptible to such treatments. Therefore, clinical trials should focus on those epigenetic markers that at some point in their disease are overexpressed or silenced.
