Genetics and epigenetics in conventional chondrosarcoma with focus on non-coding RNAs

A Summary: The detection of mutations of isocitrate dehydrogenase 1 and 2 (IDH 1/2) as tumor driver genes in chondromas and chondrosarcomas more than ten years ago was a first major step for better understanding the molecular carcinogenenesis of these rare mesenchymal tumors. Within the TCA cycle, wild-typ IDH1/2 catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (alpha-KG). IDH mutations catalyze the production of a non-physiological metabolite, D-2hydroxyglutarate (D-2HG) from alpha-KG. D-2HG can inhibit the class of alpha-KG-dependent enzymes by binding competitively to its receptor. Important enzyme families, such as the Ten-Eleven Translocation (TET) family of 5-methylcytosine hydroxylases and the Jumonji family of histone lysine deme-thylases are alpha-KG dependent. Many of the TET and Jumonji family-dependent enzymes regulate epigenetic factors, such as DNA methylation, histone modification, and nucleosome remodeling, underscoring the central role of the epigenome in cancer development. When D-2HG acts with these enzymes instead alpha-KG their functions will be in disarray with heavily hypermethylated DNA and dysregulations in histone metylation. NcRNAs have increasingly been described as a cornerstone of cancer development. Therefore this review describes exemplarily the oncogenic functions of miRNAs in chondrosarcoma in more detail. Particularly in chondrosarcomas addi-tional carcinogenic features are aquired by interactions of ncRNAs with alpha-KG-dependent epigenetic regulators. Distinct ncRNAs, miRNAs and lncRNAs alike, are involved in deregulating important cellular signalling pathways and thus contributing further to malignant transformation and development of malignant cellular traits in these rare mesenchymal tumors. This review specially empasizes the complex interactions between the world of ncRNAs and genetics and epigenetics.

Automated summary

This article reviews the important role of IDH 1/2 gene mutations in the molecular carcinogenesis of chondromas and chondrosarcomas. The mutations lead to the production of the non-physiological metabolite D-2HG, which inhibits a group of alpha-KG-dependent enzyme families, affecting the regulation of epigenetic factors. Additionally, ncRNAs are found to play a significant role in cancer development, as exemplified by the oncogenic functions of miRNAs in chondrosarcoma. Particularly in chondrosarcomas, the interactions between ncRNAs and alpha-KG-dependent epigenetic regulators contribute to the development of oncogenic traits.