Based on one of the largest genetically characterized cohort of human CS reported to date, the multi-omic classification highlighted the combined effect of the acquisition of high levels of cell cycle-related genes, the silencing of the 14q32 imprinted locus related to the downregulation of several microRNAs (including miR-154, miR-382, and miR-384, previously shown to inhibit tumor growth in bone sarcomas) and the hypermethylation of DNA at a genome-wide level, induced by IDH mutations, in the acquisition of a more aggressive grade and worse prognosis [42]. This evidence concerns the gene IDH2 and Cowden syndrome 1.