PMID- 35815721 OWN - NLM STAT- MEDLINE DCOM- 20221101 LR - 20221103 IS - 1750-3639 (Electronic) IS - 1015-6305 (Print) IS - 1015-6305 (Linking) VI - 32 IP - 6 DP - 2022 Nov TI - Molecular landscape of IDH-wild type, pTERT-wild type adult glioblastomas. PG - e13107 LID - 10.1111/bpa.13107 [doi] LID - e13107 AB - 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. CI - (c) 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. FAU - Liu, Emma Munan AU - Liu EM AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong. FAU - Shi, Zhi-Feng AU - Shi ZF AD - Hong Kong and Shanghai Brain Consortium (HSBC), Hong Kong, China. AD - Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. FAU - Li, Kay Ka-Wai AU - Li KK AUID- ORCID: 0000-0001-9588-3042 AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong. AD - Hong Kong and Shanghai Brain Consortium (HSBC), Hong Kong, China. FAU - Malta, Tathiane M AU - Malta TM AD - Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA. FAU - Chung, Nellie Yuk-Fei AU - Chung NY AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong. FAU - Chen, Hong AU - Chen H AD - Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China. FAU - Chan, Janice Yuen-Tung AU - Chan JY AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong. FAU - Poon, Manix Fung-Man AU - Poon MF AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong. FAU - Kwan, Johnny Sheung-Him AU - Kwan JS AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong. FAU - Chan, Danny Tat-Ming AU - Chan DT AD - Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong. FAU - Noushmehr, Houtan AU - Noushmehr H AD - Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, USA. FAU - Mao, Ying AU - Mao Y AD - Hong Kong and Shanghai Brain Consortium (HSBC), Hong Kong, China. AD - Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. FAU - Ng, Ho-Keung AU - Ng HK AD - Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong. AD - Hong Kong and Shanghai Brain Consortium (HSBC), Hong Kong, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220711 PL - Switzerland TA - Brain Pathol JT - Brain pathology (Zurich, Switzerland) JID - 9216781 RN - EC 1.1.1.41 (Isocitrate Dehydrogenase) RN - EC 2.7.7.49 (Telomerase) RN - EC 2.7.10.1 (ErbB Receptors) RN - 0 (Biomarkers) SB - IM MH - Humans MH - Isocitrate Dehydrogenase/genetics MH - *Glioblastoma/genetics/pathology MH - Homozygote MH - In Situ Hybridization, Fluorescence MH - *Brain Neoplasms/pathology MH - Sequence Deletion MH - *Telomerase/genetics MH - Mutation/genetics MH - ErbB Receptors/genetics MH - Biomarkers MH - Prognosis PMC - PMC9616088 OTO - NOTNLM OT - EGFR OT - IDH-wildtype OT - PDGFRA OT - TERT promoter OT - chromosome +7/-10 OT - epigenetic profiling OT - glioblastoma COIS- All authors declare no conflict no interest. EDAT- 2022/07/12 06:00 MHDA- 2022/11/02 06:00 PMCR- 2022/07/11 CRDT- 2022/07/11 06:33 PHST- 2022/01/05 00:00 [received] PHST- 2022/06/21 00:00 [accepted] PHST- 2022/07/12 06:00 [pubmed] PHST- 2022/11/02 06:00 [medline] PHST- 2022/07/11 06:33 [entrez] PHST- 2022/07/11 00:00 [pmc-release] AID - BPA13107 [pii] AID - 10.1111/bpa.13107 [doi] PST - ppublish SO - Brain Pathol. 2022 Nov;32(6):e13107. doi: 10.1111/bpa.13107. Epub 2022 Jul 11.