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The 2021 World Health Organization (WHO) grading system of isocitrate dehydrogenase (IDH)‐mutant astrocytomas relies on histological features and the presence of homozygous deletion of the cyclin‐dependent kinase inhibitor 2A and 2B (CDKN2A/B). DNA methylation profiling has become highly relevant in the diagnosis of central nervous system (CNS) tumors including gliomas, and it has been incorporated into routine clinical diagnostics in some countries. In this study, we, therefore, examined the value of DNA methylation‐based classification for prognostication of patients with IDH‐mutant astrocytomas. We analyzed histopathological diagnoses, genome‐wide DNA methylation array data, and chromosomal copy number alteration profiles from a cohort of 385 adult‐type IDH‐mutant astrocytomas, including a local cohort of 127 cases and 258 cases from public repositories. Prognosis based on WHO 2021 CNS criteria (histological grade and CDKN2A/B homozygous deletion status), other relevant chromosomal/gene alterations in IDH‐mutant astrocytomas and DNA methylation‐based subclassification according to the molecular neuropathology classifier were assessed. We demonstrate that DNA methylation‐based classification of IDH‐mutant astrocytomas can be used to predict outcome of the patients equally well as WHO 2021 CNS criteria. In addition, methylation‐based subclassification enabled the identification of IDH‐mutant astrocytoma patients with poor survival among patients with grade 3 tumors and patients with grade 4 tumors with a more favorable outcome. In conclusion, DNA methylation‐based subclassification adds prognostic information for IDH‐mutant astrocytomas that can further refine the current WHO 2021 grading scheme for these patients. [ABSTRACT FROM AUTHOR]

Background: Neuroblastoma (NB) is a complex disease, and the current understanding of NB biology is limited. Deregulation in genomic imprinting is a common event in malignancy. Since imprinted genes play crucial roles in early fetal growth and development, their role in NB pathogenesis could be suggested. Methods: We examined alterations in DNA methylation patterns of 369 NB tumours at 49 imprinted differentially methylated regions (DMRs) and assessed its association with overall survival probabilities and selected clinical and genomic features of the tumours. In addition, an integrated analysis of DNA methylation and allele-specific copy number alterations (CNAs) was performed, to understand the correlation between the two molecular events. Results: Several imprinted regions with aberrant methylation patterns in NB were identified. Regions that underwent loss of methylation in > 30% of NB samples were DMRs annotated to the genes NDN, SNRPN, IGF2, MAGEL2 and HTR5A and regions with gain of methylation were NNAT, RB1 and GPR1. Methylation alterations at six of the 49 imprinted DMRs were statistically significantly associated with reduced overall survival: MIR886, RB1, NNAT/BLCAP, MAGEL2, MKRN3 and INPP5F. RB1, NNAT/BLCAP and MKRN3 were further able to stratify low-risk NB tumours i.e. tumours that lacked MYCN amplification and 11q deletion into risk groups. Methylation alterations at NNAT/BLCAP, MAGEL2 and MIR886 predicted risk independently of MYCN amplification or 11q deletion and age at diagnosis. Investigation of the allele-specific CNAs demonstrated that the imprinted regions that displayed most alterations in NB tumours harbor true epigenetic changes and are not result of the underlying CNAs. Conclusions: Aberrant methylation in imprinted regions is frequently occurring in NB tumours and several of these regions have independent prognostic value. Thus, these could serve as potentially important clinical epigenetic markers to identify individuals with adverse prognosis. Incorporation of methylation status of these regions together with the established risk predictors may further refine the prognostication of NB patients. [ABSTRACT FROM AUTHOR]