Malignant pleural mesothelioma (MPM) is an aggressive tumor which arises from pleural layer that is characterized by resistance to conventional treatment modalities and poor prognosis [
1]. In the majority of cases, MPM is associated with work or environmental exposure to asbestos fibers [
1,
2]. Importantly, it can occur after a long latency [
3]. The incidence of MPM is increasing and is expected to reach its peak by 2020 [
4]. MPM’s molecular profile is almost unknown so that the disease is still lacking effective therapeutic prospects. Recently, it has been shown that germline
BAP1 mutations are rare events that might predispose to MPM. Furthermore, somatic
BAP1 changes are frequently reported [
5], followed by mutations in
NF2 (encoding for merlin) and
CDKN2A (encoding for p16
INK4A and p14
ARF). Comprehensive genomic analysis allowed the identification of recurrent gene fusions and splice alteration as frequent mechanisms of inactivation of
NF2,
BAP1 in MPM and reported alterations in Hippo, mTOR, histone methylation RNA helicase and p53 signaling pathways [
6]. Transcriptomic analysis demonstrated that poorest prognosis is associated to the activation of the epithelial-to-mesenchymal transition program which mainly affects sarcomatoid subtypes [
7]. Recent insight in regarding epigenetic alterations in MPM showed that they are common events during disease onset and progression [
8]. A better understanding of epigenetic mechanisms affecting MPM is, thus, mandatory to provide novel therapeutic opportunities against MPM.
On this basis, our study aimed at investigating in two relevant cohorts of MPM the expression of 5-hydroxymethylcytosine (5- hmC), an epigenetic marker and an important regulator of embryonic development and carcinogenesis [
9]. Moreover, we investigated the methylation status of the promoter of the methylthioadenosine phosphorylase (
MTAP) gene, encoding for an enzyme involved in the rescue process of methionine and adenine. Inactivation of this gene – which is known to be involved in oncogenesis of different malignancies – may occur through two different mechanisms: i) genetic deletion; ii) hypermethylation of the promoter. Many solid tumours and hematologic malignancies lack expression of the MTAP enzyme, due to either deletion of the
MTAP gene or methylation of the
MTAP promoter. Solid tumors frequently lacking MTAP include MPM, non-small cell lung cancer (NSCLC), gliomas and pancreatic cancer. The hypermethylation of
MTAP promoter is also involved in hepatocellular carcinoma as well as gastric adenocarcinoma onset [
10,
11].
MTAP is located at the
INK4 locus near the tumour suppressor gene p16
INK4A. Homozygous deletion of
CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases [
12,
13].
MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of
CDKN2A deleted cases (90%) [
11,
12,
14]. Within regard to MPM, it has been recently reported that
MTAP is frequently deleted. The combination of MTAP and BPA1 expression levels, detected by immunohistochemistry, appears to be a reliable and useful method for differentiating MPM cell from reactive mesothelial cells [
15] with a good sensitivity and 100% specificity in detecting MPM [
16].