Epigenetics of Thymic Epithelial Tumors

Abstract

Thymic epithelial tumors (TETs) arise from the epithelial cells of the thymus and consist in the 1% of all adult malignancies, despite the fact that they are the most common lesions of the anterior mediastinum. TETs can be divided mainly into thymomas, thymic carcinomas, and the rarest ad aggressive neuroendocrine forms. Despite the surgical resection is quite resolving, the diagnosis of TETs is complicated by the absence of symptoms and the clinical presentation aggravated by several paraneoplastic disorders, including myasthenia gravis. Thus, the heterogeneity of TETs prompts the search for molecular biomarkers that could be helpful for tumor characterization and clinical outcomes prediction. With these aims, several researchers investigated the epigenetic profiles of TETs. In this manuscript, we narratively review the works investigating the deregulation of epigenetic mechanisms in TETs, highlighting the need for further studies combining genetic, epigenetic, and expression data to better characterize the different molecular subtypes and identify, for each of them, the most relevant epigenetic biomarkers of clinical utility.

Non-Mutational Key Features in the Biology of Thymomas

“…Increased DNMT activity in cancer cells is associated with tumor aggressiveness and poor patient prognosis [ 60 ]. Numerous published studies, summarized in recent reviews [ 61 , 62 ], have addressed the epigenetics of TETs. Most of the available literature has focused on the potential use of DNA methylation markers to discriminate between different histologic subtypes or between THs with and without myasthenia gravis or as a prognostic indicator.…”

“…Studies analyzing global methylation patterns in TETs have found substantial hyper- or hypomethylation of CpG sites with significant correlations with the TH histologic subtype [ 4 , 63 , 64 , 65 ], GTF2I or HRAS mutation status, and mRNA and miRNA expression patterns [ 4 ]. Previous studies using a candidate gene approach revealed the hypomethylation of several tumor suppressor genes (e.g., APC1A , CDKN2A , E-cad , FHIT , hMLH1 , MGMT , RARβ , RASSF1A ) or hypermethylation of DNMT1 , DNMT3a , and DNMT3b [ 66 ] in early stage THs compared to more aggressive or late stage THs and TCs (reviewed in [ 61 , 62 ]). The specific silencing of these genes with a role in regulating cell cycle progression and DNA repair suggests an essential step during TH progression.…”

“…Non-coding RNAs (ncRNAs) play critical roles in various biological processes, diseases and tumors, and many published studies have shown that their expression patterns can be used for the accurate classification and prognostic prediction of THs. The role of ncRNAs in TETs has been addressed in several recent excellent reviews [ 61 , 62 , 83 ] and will only be briefly highlighted here. ncRNAs are produced by transcription from various genomic regions and undergo post-transcriptional maturation and modification [ 84 ].…”

Unraveling molecular networks in thymic epithelial tumors: deciphering the unique signatures

“…Epigenetic modifications, such as DNA methylation changes, aberrant expression of non-coding RNAs, and post-translational modifications of histone tails, have emerged as pivotal drivers of genomic instability and chromosomal aberrations in cancer cells ( Figure 2 ). These modifications intricately modulate the gene expression landscape, activating transposable elements, upregulating oncogenes, and silencing tumor suppressor genes, thereby fostering the onset and progression of tumorigenesis ( 76 ). Remarkably, a subset of epigenetic genes implicated in chromatin remodeling (e.g., SMARCA4), histone modifications (e.g., BAP1, SETD2, ASXL1), and DNA methylation (e.g., TET2, DNMT3A, WT1) exhibits recurrent somatic mutations.…”

PD-L1 Expression in Neoplastic and Immune Cells of Thymic Epithelial Tumors: Correlations with Disease Characteristics and HDAC Expression

“…Depending on their enzymatic activities and substrate specificities, they are classified into four classes, and their inhibition leads to a more open chromatin, allowing the access of transcription factors to regulatory sites, facilitating the activation of gene expression [18]. So far, studies have provided indirect evidence regarding the involvement of histone post-translational modifications, including deacetylation, in the pathogenesis of TETs (reviewed in [19]). Low HDAC6 expression has been correlated with a dismal prognosis of patients with TETs based on the pan-cancer analysis of TCGA, genotype-tissue expression (GTEx), and the Cancer Cell Line Encyclopedia (CCLE) datasets [20].…”