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Aims: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH‐mutant astrocytic tumours progresses to IDH‐mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH‐mutant glioblastomas. Methods: We performed an integrated molecular analysis of a mono‐centric cohort (n = 97); assessed through genome‐wide DNA methylation analysis, copy‐number profiling and targeted next generation sequencing using a neurooncology‐tailored gene panel. Results: Of these 97 IDH‐mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH‐mutant glioblastoma) and 29 emerged from a prior low‐grade lesion ('evolved' IDH‐mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH‐mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. Conclusions: This study demonstrates DNA methylation patterns in IDH‐mutant glioblastoma to be distinct from lower‐grade astrocytic counterparts but homogeneous within de novo and evolved IDH‐mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub‐stratification. [ABSTRACT FROM AUTHOR]

Aims: Paediatric low‐grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. Methods: We performed microRNA profiling on 45 fresh‐frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non‐neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. Results: One of the most markedly down‐regulated microRNAs in our supratentorial pLGGs cohort was miR‐139‐5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3‐kinase) catalytic unit, PIK3CA. We investigated the role of miR‐139‐5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR‐139‐5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated‐p70 S6 kinase (p‐p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR‐139‐5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. Conclusions: These findings provide the first evidence that down‐regulation of miR‐139‐5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling. [ABSTRACT FROM AUTHOR]