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

Abstract

Background: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). Materials and Methods: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. Results: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. Conclusions: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients.

Prognostic and Predictive Biomarkers in Gliomas

“…On the other hand, Caccese et al in a multicenter study reported that MMR protein expression status did not affect survival in HGG patients. They also showed that alteration of MMR protein expression was statistically more frequent in grade 3 gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mutant gliomas [ 164 ].…”

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

“…Despite the large difference in the genetic makeup of hypermutated tumors, it is unclear whether patients with such tumors have a different clinical course. One report suggested a longer survival [ 24 ], although other studies noted no survival differences [ 16 , 25 , 45 , 46 ] or even a trend towards poorer survival in IDH-wt rGBMs [ 40 ]. There is scarce evidence on the efficacy of treatment of hypermutated GBMs.…”

Sustained Accumulation of Blood-Derived Macrophages in the Immune Microenvironment of Patients with Recurrent Glioblastoma after Therapy

“…In terms of the presence of lymphocytes, we found an increased frequency of CD8 + T cells, both in the central and marginal areas of tumor relapses ( Figure 2 A), a finding confirmed by multispectral imaging and reported by others [ 13 ]. All the patients in our study underwent radiochemotherapy with temozolomide treatment following surgery, and it is well known that this alkylating drug induces hypermutations in gliomas by alteration of mismatch repair system [ 28 ], with subsequent increased mutational load [ 29 ]. This, in turn, correlates with higher levels of neoantigens, which is the prerequisite for an adaptive immune response.…”