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

Abstract

Diffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency. None of the tumors exhibited a combined 1p/19q deletion. These primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) were histologically high-grade and were mainly found in children, adolescents and young adults (median age 14 years). Mismatch repair deficiency syndromes (Lynch or Constitutional Mismatch Repair Deficiency Syndrom (CMMRD)) were clinically diagnosed and/or germline mutations in DNA mismatch repair genes (MLH1, MSH6, MSH2) were found in all cases, except one case with a family and personal history of colon cancer and another case with MSH6-deficiency available only as recurrent tumor. Loss of at least one of the mismatch repair proteins was detected via immunohistochemistry in all, but one case analyzed. Tumors displayed a hypermutant genotype and microsatellite instability was present in more than half of the sequenced cases. Integrated somatic mutational and chromosomal copy number analyses showed frequent inactivation of TP53, RB1 and activation of RTK/PI3K/AKT pathways. In contrast to the majority of IDH-mutant gliomas, more than 60% of the samples in our cohort presented with an unmethylated MGMT promoter. While the rate of immuno-histochemical ATRX loss was reduced, variants of unknown significance were more frequently detected possibly indicating a higher frequency of ATRX inactivation by protein malfunction. Compared to reference cohorts of other IDH-mutant gliomas, primary mismatch repair-deficient IDH-mutant astrocytomas have by far the worst clinical outcome with a median survival of only 15 months irrespective of histological or molecular features. The findings reveal a so far unknown entity of IDH-mutant astrocytoma with high prognostic relevance. Diagnosis can be established by aligning with the characteristic DNA methylation profile, by DNA-sequencing-based proof of mismatch repair deficiency or immunohistochemically demonstrating loss-of-mismatch repair proteins.

Prognostic and Predictive Biomarkers in Gliomas

“…PMMRDIA were histologically high-grade and were mainly found in younger patients (median age 14 years) and all of them had a defective MMR system. They also reported that compared to reference cohorts of other IDH-mutant gliomas, PMMRDIA had by far the worst clinical outcome with a median survival of only 15 months irrespective of histological or molecular features [ 163 ].…”

Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1

“…DNA extraction was performed as previously described [35]. DNA methylation profiles were generated using the Infinium HumanMethylation450 (450 k) or Infinium MethylationEPIC (850 k) BeadChip array (Illumina, San Diego, USA) according to the manufacturer's instructions.…”

“…Reference cases were selected based on a high classifier score (> 0.9) in the brain tumor classifier. Methylation of the O 6 -alkylguanine DNA alkyltransferase (MGMT) promoter region was calculated as described previously [35].…”

DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology

“… 34 This genetic distinction was confirmed with DNA methylation profiling and has recently been refined to identify a clinically-distinct subtype (e.g. mismatch repair-deficient 35 ). For many of the newly-described tumor types, however, methylation profiling has largely served as a tool for discovery.…”