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.
Highlights
The discovery of mutations in isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) genes in glial brain tumors critically shaped the understanding of the clinical importance of molecular differences in gliomas1 3 Vol.:(0123456789)Acta Neuropathologica (2021) 141:85–100[4, 37, 51]
Given the well-known favorable outcome of diffuse IDHmutant gliomas compared to malignant diffuse IDH-wt gliomas, on the one hand, and the known temozolomideresistant phenotype of mismatch repair (MMR)-deficient cells, on the other hand, we addressed the question whether the clinical outcome of primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) significantly differs from that of other IDH-mutant gliomas
Our study reveals that IDH-mutant astrocytomas occurring in children and young adults with germline mutations in MMR genes (Lynch and CMMRD) constitute a distinct entity which should be separated from other IDH-mutant gliomas
Summary
The discovery of mutations in isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) genes in glial brain tumors critically shaped the understanding of the clinical importance of molecular differences in gliomas1 3 Vol.:(0123456789)Acta Neuropathologica (2021) 141:85–100[4, 37, 51]. The WHO classification of CNS tumors from 2016 recognizes the following types: diffuse astrocytoma, IDH-mutant (WHO grade II), anaplastic astrocytoma, IDH-mutant (WHO grade III) and glioblastoma, IDH-mutant (WHO grade IV), oligodendroglioma, IDHmutant and 1p/19q-codeleted (WHO grade II) and anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted (WHO grade III) [35]. By DNA methylation profiling, IDH-mutant gliomas are generally clearly distinguishable from IDH-wt tumors by the CpG island methylator phenotype (G-CIMP) [50]. The current version of the DNA methylation-based CNS tumor classification system distinguishes three subclasses within the methylation class family glioma, IDH-mutant: subclass astrocytoma (mostly accounts for WHO grade II and III), subclass high-grade astrocytoma (mostly accounts for WHO grade III and IV) and subclass 1p/19q-codeleted oligodendroglioma (including both WHO grade II and III) [14]. Recently infratentorial astrocytomas were found to be a discrete subgroup within IDH-mutant astrocytomas that form a distinct methylation cluster [5]
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