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

Abstract

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 (from 96 patients) with known tumor mutation burden (TMB), while blinded to TMB data. Cases included 70 grade IV GBMs, 13 grade III astrocytomas, 4 grade II astrocytomas (3 diffuse astrocytomas and 1 pleomorphic xanthoastrocytoma), 1 grade I pilocytic astrocytoma, 2 grade III oligodendrogliomas, 7 grade II oligodendrogliomas, and 3 grade I glioneuronal tumors. Eight of 100 tumors showed loss of one or more MMR proteins by IHC, and all 8 were hypermutated. Among the remaining 92 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 for DNA MMR IHC compared to the gold standard of TMB were 99, 89, and 100%, respectively. The strongest correlates with hypermutation were prior TMZ treatment, MGMT promoter methylation, and IDH1 mutation. Among the 8 MMR-deficient hypermutated gliomas, 4 (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.

Mismatch-Repair Protein Expression in High-Grade Gliomas: A Large Retrospective Multicenter Study

“…Indeed, Hodges et al [ 3 ] demonstrated that immunohistochemical loss of at least one MMR protein expression was associated with the hypermutation profile in glioma patients. This correlation was confirmed in further recent studies [ 4 , 5 , 6 ]. Immune checkpoint inhibitors, in particular Nivolumab and Pembrolizumab (anti PD-1), were tested in several types of tumors with MMR deficiency (MMRd), showing impressive antitumor activity [ 7 , 8 , 9 , 10 , 11 , 12 ]; based on these results, the FDA approved the use of pembrolizumab in patients with any solid tumor with MMRd after progression from prior chemotherapy [ 13 ].…”

“…In particular, the presence of mutated IDH can affect epigenetic alterations and lead to a higher probability of alteration of MMR protein expression in grade 3 gliomas. Moreover, immunohistochemical loss of MMR protein expression may be useful to detect hypermutated cancers as demonstrated by McCord et al [ 6 ]; in this study, the authors showed that IHC loss of MMR proteins can detect hypermutated gliomas with high sensitivity and specificity; yet, in this study, 9 out of 100 gliomas were hypermutated and 8 out of 9 had complete loss of expression of at least one MMR protein. All hypermutated patients had previously received temozolomide.…”

Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study

“…The association between MMR status and hypermutation is still unclear in gliomas [ 6 , 8 , 18 ]. The high frequency of hypermutated gliomas in our cohort, which is much higher than the 3.5% previously reported in glioblastoma [ 5 ], may suggest that the immunohistochemical loss of MMR proteins is useful to detect hypermutated tumors, as recently proposed by McCord et al [ 8 ].…”

“…The association between MMR status and hypermutation is still unclear in gliomas [ 6 , 8 , 18 ]. The high frequency of hypermutated gliomas in our cohort, which is much higher than the 3.5% previously reported in glioblastoma [ 5 ], may suggest that the immunohistochemical loss of MMR proteins is useful to detect hypermutated tumors, as recently proposed by McCord et al [ 8 ]. Although 8/9 hypermutated gliomas in McCord et al [ 8 ] had MMR immunohistochemical loss and MMR mutations, MSI status was not explored and whether hypermutated gliomas identified by means of MMR immunohistochemical loss are responsive to immune check point inhibitors remained unsolved.…”

Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis

“…Promoter methylation-mediated silencing of MGMT is associated with increased sensitivity towards temozolomide and present in the vast majority of IDH-mutant gliomas [ 19 ]. A fraction of recurrent IDH-mutant gliomas develops resistance against TMZ by acquiring mutations in MMR genes, leading secondarily to a hypermutated genotype [ 10 , 13 , 36 , 44 , 47 ].…”