**1. Introduction**

Human malignant pleural mesothelioma (MPM) is an invariably fatal tumor due to its heterogeneity, growing from the serous surfaces of the pleura. Many factors are involved in its occurrence, such as exposure to asbestos fibers and simian virus 40; these factors being those that are strongly associated with the tumorigenesis of this disease. The annual incidence of MPM is relatively low, estimated in a range of 0.6–30/10,00,000, but the global occurrence is expected to increase continuously in future years [1]. MPM is extremely heterogeneous in its morphology and molecular phenotypes. The latency period for MPM development is 10–50 years after asbestos exposure. The prognosis for MPM is generally poor, with a median survival time of 12 months from diagnosis [1].

Intratumor heterogeneity refers to a mixture of phenotypic, functional, and genetic differences within cancer cells with various differentiation or hierarchical statuses

within the tumor. It is a common feature in most tumors. This heterogeneity has been considered the greatest obstacle to the effectiveness of most cancer therapies, manifesting itself in its sensitivity to different therapies. Several studies have been focused on genetic alterations as part of the mechanism of tumoral cells for the generation and maintenance of this heterogeneity. In addition, some other studies show the role of epigenetic modifications involved in its heterogeneity. Despite this, there is scarce information about epigenetic modifications that could explain this process [1, 2].

Epigenetic modifications are heritable and stable alterations of genes that do not change the DNA sequence, including DNA methylation, histone modification, and non-coding RNA interference modifications. DNA methylation has been extensively studied in the development of cancer. On the one hand, hypermethylation in cancerrelated promoter genes induces the silencing or downregulation of tumor suppressor genes and repair genes. On the other hand, hypomethylation of DNA leads to activation of oncogenes and genomic instability. Several authors suggest that aberration in DNA methylation may play an important role on tumor cells heterogeneity [3–5].

The exact mechanisms by which asbestos fibers promote the development of cancer are unknown, however, the most accepted theory is the induction of chronic inflammation and signaling pathways in the transformation of reactive oxygen species generated by asbestos fibers. Therefore, this chapter will address an overview of the epigenetic profile of MPM and the mechanisms that promote epigenetic modifications where asbestos fibers might play an important role.
