Integrated molecular characterization of IDH‐mutant glioblastomas.

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]