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.