KMT2D, a histone methyltransferase that regulates H3 lysine 4, was also strongly mutated in 69% out of 39 aggressive cSCC samples analyzed through exome and targeted sequencing for identification of novel potential driver mutations [28], and in vitro studies have shown that KMT2D mutated cells display genomic instability and increased transcriptional stress [54]. This evidence concerns the gene KMT2D and skin squamous cell carcinoma.