The efficacy of DNA MMR enzyme immunohistochemistry as a screening test for hypermutated gliomas

A subset of gliomas has DNA repair defects that lead to hypermutated genomes. While such tumors are resistant to alkylating chemotherapies, they may also express more mutant neoantigens on their cell surfaces, and thus be more responsive to immunotherapies. A fast, inexpensive method of screening for hypermutated gliomas would therefore be of great clinical value. Since immunohistochemistry (IHC) for the DNA mismatch repair (MMR) proteins Msh2, Msh6, Mlh1, and Pms2 is already used to screen for hypermutated colorectal cancers, we sought to determine whether that panel might have similar utility in gliomas. MMR IHC was scored in 100 WHO grade I-IV gliomas with known tumor mutation burdens (TMB), while blinded to TMB data. Eight of 100 cases showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 94 gliomas with intact MMR IHC, only one was hypermutated; that tumor had an inactivating mutation in another DNA repair gene, ATM. Overall accuracy, sensitivity, and specificity were 99%, 89%, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among MMR-deficient hypermutated gliomas, 50% contained both MMR-lost and MMR-retained tumor cells. Together, these data suggest that MMR IHC could be a viable front-line screening test for gliomas in which immunotherapy is being considered. They also suggest that not all cells in a hypermutated glioma may actually be MMR-deficient, a finding that might need to be considered when treating such tumors with immunotherapies.