Furthermore, the interplay of an epigenetic hallmark, such as DNA methylation, as negatively correlated with the H3K4me3 mark may explain the hypermethylation in the hypermutated samples.32 Meanwhile, frequent depletion of the H3K36 methyltransferase SETD2 (21%) and H3K4 methyltransferase SETD1B (34%) in CRC and H3K4 methyltransferase SETD1A (21%) in STAD, which are all associated with gene transcription, elongation, or alternative splicing,33, 34, 35, 36 may also play a role in remodeling consistent hypermutated expression and DNA methylation patterns. Here, SETD2 is linked to colorectal carcinoma.