RB1 and neoplasm: On the other hand, promoter hypermethylation of genes belonging to the RB1 pathway has been suggested to be involved in the decrease in RB1-related functions [27,40] Indeed, two studies revealed hypermethylation of the p16INK4a gene promoter, which was associated with a negative or decreased p16INK4a expression, and may impair the RB1-mediated control of cell cycles and tumor cell growth in a minority of HGOS [41,42,43,44].