Open AccessMolecular landscape of IDH ‐wild type, p TERT ‐wild type adult glioblastomas
Author(s) -
Liu Emma Munan,
Shi ZhiFeng,
Li Kay KaWai,
Malta Tathiane M.,
Chung Nellie YukFei,
Chen Hong,
Chan Janice YuenTung,
Poon Manix FungMan,
Kwan Johnny SheungHim,
Chan Danny TatMing,
Noushmehr Houtan,
Mao Ying,
Ng HoKeung
Publication year - 2022
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.13107
Subject(s) - pdgfra , isocitrate dehydrogenase , idh1 , biology , cancer research , epidermal growth factor receptor , fluorescence in situ hybridization , glioma , oncology , pathology , microbiology and biotechnology , medicine , cancer , mutation , stromal cell , genetics , chromosome , gene , gist , biochemistry , enzyme
Telomerase reverse transcriptase ( TERT ) promoter (p TERT ) 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) ( IDH wt), p TERT wt glioblastomas are not well known. We recruited 72 adult IDH wt, p TERT wt 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 IDH wt, p TERT mutant (mut) glioblastomas, suggesting that p TERT mutation on its own is not a prognostic factor among IDH wt 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 IDH wt, p TERT mut 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 p TERT wt, so the three molecular properties of EGFR amplification, +7/−10, and p TERT mutation may not cover all IDH wt 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 IDH wt, p TERT wt glioblastomas show epigenetic clustering different from IDH wt, p TERT mut glioblastomas, and IDHwt glioblastomas which are p TERTwt 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.