CTLA4 and colorectal carcinoma: As previously mentioned, one of the leading causes of hypermutation in CRC is a defect in the DNA MMR system, which results in MSI-H tumors that strongly express various immunological checkpoint proteins, including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), PD-1, and programmed-death ligand 1 (PD-L1).