Mismatch repair protein mutations in isocitrate dehydrogenase (IDH)-mutant astrocytoma and IDH-wild-Type glioblastoma

Background: Mutations in mismatch repair (MMR) genes (MSH2, MSH6, MLH1, and PMS2) are associated with microsatellite instability and a hypermutator phenotype in numerous systemic cancers, and germline MMR mutations have been implicated in multi-organ tumor syndromes. In gliomas, MMR mutations can function as an adaptive response to alkylating chemotherapy, although there are well-documented cases of germline and sporadic mutations, with detrimental effects on patient survival. Methods: The clinical, pathologic, and molecular features of 18 IDH-mutant astrocytomas and 20 IDH-wild-Type glioblastomas with MMR mutations in the primary tumor were analyzed in comparison to 361 IDH-mutant and 906 IDH-wild-Type tumors without MMR mutations. In addition, 12 IDH-mutant astrocytomas and 18 IDH-wild-Type glioblastomas that developed MMR mutations between initial presentation and tumor recurrence were analyzed in comparison to 50 IDH-mutant and 104 IDH-wild-Type cases that remained MMR-wild-Type at recurrence. Results: In both IDH-mutant astrocytoma and IDH-wild-Type glioblastoma cohorts, the presence of MMR mutation in primary tumors was associated with significantly higher tumor mutation burden (TMB) (P<.0001); however, MMR mutations only resulted in worse overall survival in the IDH-mutant astrocytomas (P=.0069). In addition, gain of MMR mutation between the primary and recurrent surgical specimen occurred more frequently with temozolomide therapy (P=.0073), and resulted in a substantial increase in TMB (P<.0001), higher grade (P=.0119), and worse post-recurrence survival (P=.0022) in the IDH-mutant astrocytoma cohort. Conclusions: These results suggest that whether present initially or in response to therapy, MMR mutations significantly affect TMB but appear to only influence the clinical outcome in IDH-mutant astrocytoma subsets.