Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations

Abstract

Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.

Keywords: epigenome; malignant pleural mesothelioma; target therapies.

Figure 1

Inhalation of asbestos fibers causes an inflammatory response in the lungs that results in the chronic production of ROS and RNS. These reactive species collide with biological molecules, damaging them. In particular, 8-OhdG can generate DNA base mispairing, resulting in G-to-T transversions. Moreover, DNA methylation is vulnerable to asbestos fibers that, indeed, are a cause of tumor suppressor genes (TSGs), promoting hypermethylation and subsequent silencing. Additionally, mesothelial cells exposed to asbestos undergo necrosis, releasing HMGB1 into the intercellular space and thus recruiting macrophages and stimulating the chronic inflammation response. Activated macrophages release TNF-alpha and other inflammatory cytokines that result in NF-kB. Activation leads to consequent survival of HM cells with genetic damage. These two mechanisms work together to trigger tumor formation and growth. List of abbreviations: ROS—reactive oxygen species, RNS—reactive nitrogen species, TSGs—tumor suppressor genes, HMGB1—high-mobility group box 1, TNFa—tumor necrosis factor alpha.