Genomic profiles of IDH-mutant gliomas: MYCN amplified IDH-mutant astrocytoma had the worst prognosis and true mixed oligoastrocytoma does not exist

Abstract

Abstract Background This study aims to find any ambiguous genetic outlier for “oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)” and “astrocytoma, IDH-mutant (A_IDH_mut)” and to redefine the genetic landscape of IDH-mutant gliomas. Methods: The next-generation sequencing (NGS) using a brain tumor-targeted gene panel, methylation profiles, and clinicopathological features were analyzed in O_IDH_mut (n = 74) in 70 patients and A_IDH_mut (n = 95) in 90 patients. Results Three had ambiguous genetic profiles for either O_IDH_mut or A_IDH_mut. Two were unusual TP53-mutant O_IDH_mut, validated with the DKFZ methylation classifier (MC) (score: 0.98). The remaining one was a 1p/19q-codeleted and TERTp-mutant A_IDH_mut, which also had TP53 and CIC mutations. This case was matched to O_IDH_mut (Score: 0.75) by the DKFZ-MC v.11b4 algorithm but was corrected to A_IDH_mut_HG (high-grade) (Score: 0.84) using the updated DKFZ-MC v.12.5. The remaining 97.3% and 98.9% of O_IDH_mut and A_IDH_mut had a classic genomic landscape. The patients with MYCN amplified and/or CDKN2A/2B homozygously deleted A_IDH_mut had a worse prognosis than those without these genes’ alterations. Conclusion: CIC and/or FUBP1 mutations were detected in 93.2%, and MGMTp methylation was detected in 95.9% of O_IDH_mut patients. Accepting that 1p/19q codeletion and TP53 mutations are not 100% mutually exclusive, as are the three exceptional cases mentioned above, would be of great help in diagnosing the two subtypes of IDH-mutant diffuse glioma. In histopathologically or genetically ambiguous cases, MC can be an objective tool to avoid a diagnosis of NOS (not otherwise specified) or NEC (not elsewhere classified), as well as tumor classification. The authors have not encountered a true mixed oligoastrocytoma using an integrated diagnosis of genetic and methylation profiles. MYCN amplification, like CDKN2A/2B homozygous deletion, should be included in the genetic criteria for grade 4 A_IDH_mut.