Molecular landscape of IDH-wild type, pTERT-wild type adult glioblastomas

Abstract

Telomerase reverse transcriptase (TERT) promoter (pTERT) mutation has often been described as a late event in gliomagenesis and it has been suggested as a prognostic biomarker in gliomas other than 1p19q codeleted tumors. However, the characteristics of isocitrate dehydrogenase (IDH) wild type (wt) (IDHwt), pTERTwt glioblastomas are not well known. We recruited 72 adult IDHwt, pTERTwt glioblastomas and performed methylation profiling, targeted sequencing, and fluorescence in situ hybridization (FISH) for TERT structural rearrangement and ALT (alternative lengthening of telomeres). There was no significant difference in overall survival (OS) between our cohort and a the Cancer Genome Atlas (TCGA) cohort of IDHwt, pTERT mutant (mut) glioblastomas, suggesting that pTERT mutation on its own is not a prognostic factor among IDHwt glioblastomas. Epigenetically, the tumors clustered into classic-like (11%), mesenchymal-like (32%), and LGm6-glioblastoma (GBM) (57%), the latter far exceeding the corresponding proportion seen in the TCGA cohort of IDHwt, pTERTmut glioblastomas. LGm6-GBM-clustered tumors were enriched for platelet derived growth factor receptor alpha (PDGFRA) amplification or mutation (p = 0.008), and contained far fewer epidermal growth factor receptor (EGFR) amplification (p < 0.01), 10p loss (p = 0.001) and 10q loss (p < 0.001) compared with cases not clustered to this group. LGm6-GBM cases predominantly showed ALT (p = 0.038). In the whole cohort, only 35% cases showed EGFR amplification and no case showed combined chromosome +7/-10. Since the cases were already pTERTwt, so the three molecular properties of EGFR amplification, +7/-10, and pTERT mutation may not cover all IDHwt glioblastomas. Instead, EGFR and PDGFRA amplifications covered 67% and together with their mutations covered 71% of cases of this cohort. Homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A)/B was associated with a worse OS (p = 0.031) and was an independent prognosticator in multivariate analysis (p = 0.032). In conclusion, adult IDHwt, pTERTwt glioblastomas show epigenetic clustering different from IDHwt, pTERTmut glioblastomas, and IDHwt glioblastomas which are pTERTwt may however not show EGFR amplification or +7/-10 in a significant proportion of cases. CDKN2A/B deletion is a poor prognostic biomarker in this group.

Keywords: EGFR; IDH-wildtype; PDGFRA; TERT promoter; chromosome +7/−10; epigenetic profiling; glioblastoma.

FIGURE 1

Oncoprint of the clinical features and molecular alterations of IDHwt, pTERTwt glioblastomas. IDHwt, isocitrate dehydrogenase wild type; pTERT, telomerase reverse transcriptase promoter;

FIGURE 2

Survival analyses. (A) The survival outcome of IDHwt, pTERTwt glioblastomas in this study cohort and IDHwt, pTERTmut glioblastomas in TCGA cohort showed no difference. (B) OS and (C) PFS were not different among methylation subtypes in this study cohort. (D) IDHwt, pTERTwt glioblastomas of this study cohort harboring cyclin dependent kinase inhibitor 2A (CDKN2A)/B loss had a shorter OS. (E) CDKN2A/B loss showed a trend toward a shorter PFS. IDHwt, isocitrate dehydrogenase wild type; OS, overall survival; PFS, progression‐free survival; pTERT, telomerase reverse transcriptase promoter.

FIGURE 3

Representative FISH photos for ALT and TERT structural rearrangement. (A) A positive case for ALT. Large, ultra‐bright, intranuclear foci of signals were present. (B) A negative case for ALT. (C) A positive case for TERT rearrangement. Dual color break‐apart probes were designed to detect TERT structural rearrangement. Split signals were observed in the TERT‐rearranged case. (D) A negative case for TERT rearrangement, displaying merged (yellow) signals. ALT, alternative lengthening of telomeres; TERT, telomerase reverse transcriptase;