Adult IDH wild-type lower-grade gliomas should be further stratified

Abstract

Background: Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically.

Methods: Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined.

Results: EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification.

Conclusion: Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.

Keywords: IDH wild-type; MYB amplification; glioma; molecular grade; prognosis.

Fig. 1

Grid figure summarizing frequency and distribution of the clinical as well as molecular markers of IDH wild-type lower-grade gliomas. Representative radiologic images of IDH wild-type lower-grade gliomas harboring each of the molecular markers are shown. Cases without survival data are not included in this figure.

Fig. 2

Kaplan–Meier survival analysis of TERT mutation, EGFR amplification, H3F3A K27M mutation, BRAF mutation, MYB amplification, and different molecularly graded subgroups. Survival analysis of different biomarkers revealed that (A) TERTp mutation, (B) EGFR amplification, and (C) H3F3A K27M mutation were associated with shorter OS compared with their wild-type or non-amplified counterparts (P < 0.001, P = 0.003, and P = 0.009, respectively). (D) BRAF V600E mutant tumors tended to have better prognosis compared with BRAF wild-type tumors (P = 0.13). (E) There was no statistical survival difference between the MYB amplified and non-amplified tumors (P = 0.64). (F) Molecularly lower-grade tumors (IDH wild-type lower-grade gliomas lacking EGFR amplification, H3F3A mutation, and TERT promoter mutation) had longer OS compared with molecularly high-grade tumors (IDH wild-type lower-grade gliomas harboring either EGFR amplification, H3F3A K27M, or TERT promoter mutation) (P < 0.001). (G) Kaplan–Meier analysis of prognostic value revealed that MYB amplification appeared to be a favorable prognosticator in molecularly lower-grade gliomas. (H) The prognostic split was more obvious within grade II gliomas. Abbreviations: amp, amplified; non-amp, non-amplified.