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.
Highlights
Gliomas are the most common tumors to arise from the brain parenchyma in adults [20]
When gliomas are challenged with TMZ, recurrent subclones often emerge with inactivating mutations in genes encoding DNA mismatch repair (MMR) enzymes, most
Characteristics of tumors and patients in the cohort The cohort consisted of 100 gliomas, diagnosed in 96 patients (44 male, 52 female) with Next generation sequencing (NGS) and Tumor mutation burden (TMB) data
Summary
Gliomas are the most common tumors to arise from the brain parenchyma in adults [20]. When gliomas are challenged with TMZ, recurrent subclones often emerge with inactivating mutations in genes encoding DNA mismatch repair (MMR) enzymes, most commonly MSH2, MSH6, MLH1, and PMS2. Loss of function in these genes leads to failure of MMR mechanisms, which is essential for inducing programmed cell death in tumor cells damage by temozolomide, contributing to temozolomide resistance in recurrent tumors [6, 12, 30]. Tumor mutation burden (TMB) is normally ~ 1 mutation per megabase (Mb) of DNA [1], but MMR defects can lead to a high mutation burden, which has previously been defined as TMB > 20 mutations/Mb DNA [11,12,13]. Hypermutated tumor cells tend to display more mutant proteins on their surfaces, making them potentially more vulnerable to immunotherapies like PD-1 and PD-L1 checkpoint
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