Evaluation Of Mismatch Repair Gene Expression By Immunohistochemistry May Detect Early Phase Of Mmr Deficiency In Recurrent Gliomas

Abstract BACKGROUND Mismatch Repair (MMR) Deficiency is common in recurrent gliomas from IDH-mutant and IDH-wild-type tumors. Emergence of MMR deficit is strongly associated with the chemotherapy using TMZ, and it is considered to be a key mechanism of acquiring resistance to TMZ. Several studies showed MMR protein loss detected by immunohistochemistry was well concordant with molecular genetics sequencing data, and sometimes even more reliable in detecting MMR functional deficit. Here we evaluated Mismatch Repair protein expression by immunohistrochemistry for the pairs of primary and recurrent gliomas. METHODS We investigated the expression of 4 MMR proteins (MLH1/MSH2/MSH6/PMS2) in 37 cases of paired primary-recurrent gliomas (7 grade II & III astrocytomas, 16 grade II & III oligodendrogliomas, and 14 glioblastomas). Clinical information including history of chemo-radiotherapy after primary surgery were collected retrospectively. RESULTS Except for one case of GBM, all primary tumors retained 4 MMR proteins. 10 of 37 recurrent tumors lost one or more MMR protein expression (4 GBM 3 astrocytoma, 3 oligodendroglioma), including one case in which primary tumor already had MSH2/MSH6 loss. 2 recurrent GBM lost MMR protein expression homogenously, while in other 8 tumors, the patterns of MMR protein loss were heterogenous. 8 of 10 tumors that lost MMR protein expression were recurrence after TMZ treatment. CONCLUSION Although the interpretation of the heterogenous loss of MMR protein expression is somewhat difficult, the immunohistochemical evaluation of MMR proteins appears to be feasible, and may be able to detect early phase of MMR deficiency and the rise of hypermutator phenotype.