| Autor: |
Wong QH; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China., Li KK; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China., Wang WW; Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Malta TM; Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA., Noushmehr H; Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA., Grabovska Y; Division of Molecular Pathology, The Institute of Cancer Research, London, UK., Jones C; Division of Molecular Pathology, The Institute of Cancer Research, London, UK., Chan AK; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China., Kwan JS; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China., Huang QJ; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China., Wong GC; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China., Li WC; Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Liu XZ; Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Chen H; Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China., Chan DT; Division of Neurosurgery, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong., Mao Y; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. maoying@fudan.edu.cn., Zhang ZY; Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. neurozzy@foxmail.com., Shi ZF; Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. shizhifeng@fudan.edu.cn., Ng HK; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. |
| Abstrakt: |
WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERT promoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFR amplification, combined +7/-10, and TERT promoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRX mutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMT promoter methylation were independent good prognosticators for OS (p = 0.022 and p = 0.002, respectively) and TP53 mutation was an independent poor prognosticator (p = 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/B was not correlated with OS (p = 0.197) and PFS (p = 0.278). PDGFRA amplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p = 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRX involvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMT promoter methylation, and TP53 mutation are useful prognostic adjuncts. |
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