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

Timothy E Richardson; Raquel T Yokoda; Omid Rashidipour; Meenakshi Vij; Matija Snuderl; Steven Brem; Kimmo J Hatanpaa; Samuel K McBrayer; Kalil G Abdullah; Melissa Umphlett; Jamie M Walker; Nadejda M Tsankova

doi:10.1093/noajnl/vdad085

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

Neurooncol Adv. 2023 Jul 12;5(1):vdad085. doi: 10.1093/noajnl/vdad085. eCollection 2023 Jan-Dec.

Authors

Affiliations

¹ Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Department of Pathology, New York University Langone Health, New York, New York, USA.
³ Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁵ Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁶ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁷ Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁸ Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Abstract

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.

Keywords: astrocytoma; chromosomal instability; genomic instability; glioblastoma; mismatch repair deficit.