Targeted next‐generation sequencing of adult gliomas for retrospective prognostic evaluation and up‐front diagnostics

Abstract

Aims We aimed to reclassify a population‐based cohort of 529 adult glioma patients to evaluate the prognostic impact of the 2016 World Health Organization (WHO) central nervous system tumour classification. Moreover, we evaluated the feasibility of gene panel next‐generation sequencing (NGS) in daily diagnostics of 225 prospective glioma patients. Methods The retrospective cohort was reclassified according to WHO 2016 criteria by immunohistochemistry for IDH‐R132H, fluorescence in situ hybridization for 1p/19q‐codeletion and gene panel NGS. All tumours of the prospective cohort were subjected to NGS analysis up‐front. Results The entire population‐based cohort was successfully reclassified according to WHO 2016 criteria. NGS results were obtained for 98% of the prospective patients. Survival analyses in the population‐based cohort confirmed three major prognostic subgroups, that is, isocitrate dehydrogenase (IDH)‐mutant and 1p/19q‐codeleted oligodendrogliomas, IDH‐mutant astrocytomas and IDH‐wildtype glioblastomas. The distinction between WHO grade II and III was prognostic in patients with IDH‐mutant astrocytoma. The survival of patients with IDH‐wildtype diffuse astrocytomas carrying TERT promoter mutation and/or EGFR amplification overlapped with the poor survival of IDH‐wildtype glioblastoma patients. Conclusions Gene panel NGS proved feasible in daily diagnostics. In addition, our study confirms the prognostic role of glioma classification according to WHO 2016 in a large population‐based cohort. Molecular features of glioblastoma in IDH‐wildtype diffuse glioma were linked to poor survival corresponding to IDH‐wildtype glioblastoma patients. The distinction between WHO grade II and III retained prognostic significance in patients with IDH‐mutant diffuse astrocytic gliomas.

Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations

“…Interestingly, mutIDH1/2 do not appear to confer survival benefits in AML, 28 , 240 chondrosarcoma, 24 , 66 or ICC 37 , 241 but appear to do so in glioma. 242 Additionally, in chondrosarcoma, the response to radiation treatment does not correlate with mutIDH1/2-status. 243 Thus, the current understanding of mutIDH1/2 in relation to redox homeostasis is that it is cancer-type dependent.…”

Prognostic stratification for IDH-wild-type lower-grade astrocytoma by Sanger sequencing and copy-number alteration analysis with MLPA

“…The survival curve of DAs was definitely favourable compared with AAs in the early course, and the generalized Wilcoxon test showed a significant difference. Taking IDH -mutation status into consideration, WHO grade was reported as a significant factor for OS in lower-grade gliomas 11 , 24 , 25 , and one of the studies showed that WHO grade had higher prognostic value in IDH -wild-type astrocytomas compared with in IDH -mutant astrocytomas, with the authors proposing histological mitotic count as a significant predictor of prognosis 24 . This fact supports the importance of histological grading systems, especially for IDH -wild-type astrocytoma.…”

Prognostic Stratification for IDH-wild-type Lower-grade Astrocytoma by Sanger Sequencing and Copy-number Variation Analysis with MLPA.

“…The survival curve of DAs was de nitely favourable compared with AAs in the early course, and the generalized Wilcoxon test showed a signi cant difference. Taking IDH-mutation status into consideration, WHO grade was reported as a signi cant factors for OS in lowergrade gliomas, 11,24,25 and one of the studies showed that WHO grade had larger prognostic value in IDHwild-type astrocytomas compared with in IDH-mutant astrocytomas, with the authors proposing histological mitotic count as a signi cant predictor of prognosis. 24 This fact supports that histological grading systems remain important, especially for IDH-wild-type astrocytoma.…”