Abstract
AIMS: The DNA mismatch repair (MMR) system is critical for genomic stability correcting errors generated during DNA replication with germline pathogenic variants (PVs) causing Lynch syndrome. Although acquired MMR deficiency is associated with temozolomide resistance, the incidence in treatment naïve tumours is unknown and not routinely screened for. Here we present three MMR deficient gliomas and describe their comprehensive molecular profile. METHOD: Thirteen gliomas; 9/34 that had undergone sequencing of 50 cancer-associated genes and found to have frameshift/multiple point PVs, indicative of defective MMR, and four MSI-high tumours, identified following microsatellite analysis for 1p/19q co-deletion as part of routine care, were selected for analysis. MMR expression was then assessed by immunohistochemistry. Seven tumours showed loss of one or more MMR proteins and were molecularly characterised using PCR-based Promega MSI analysis and NGS-based Illumina TruSight500 panel. RESULTS: Pathogenic variants in MMR genes and hypermutated phenotypes (TMB > 10mutations/Mb) were identified in three cases. One individual harboured an additional POLE PV resulting in an ultra-hypermutated phenotype (>100mutations/Mb). Two MMR PVs were germline, leading to a new diagnosis of Lynch syndrome. Only one of three tumours was found to be MSI-high using the Promega MSI analysis whilst all three were identified as MSI-high using TruSight500 MSI calling algorithms. CONCLUSION: We describe the comprehensive molecular profile of seven treatment naïve gliomas, three being MMR deficient. We show TruSight500 to be more sensitive and reliable for detecting MSI compared to Promega. Given the implications, this additional analysis should be considered as part of the molecular report on all gliomas.