Clinicopathological and molecular landscape of 5-year IDH-wild-type glioblastoma survivors: a multicentric retrospective study
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PROVIDER: PRJNA962547 | ENA |
REPOSITORIES: ENA
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Project description:Background: Less than 5% of glioblastoma multiforme (GBM) patients survive more than 5-years (long-term survivors, LTS). Nevertheless, the molecular fingerprint of LTS remains uncharted. We aimed to characterize LTS by clinicopathological assessment, DNA methylation (DNAm)/Copy Number Variation (CNV) and mutation profiling. Methods: This multicentric project proposed by Alliance Against Cancer was coordinated by Fondazione IRCCS Istituto Neurologico Carlo Besta. One-hundred forty-two LTS patients were screened, and samples centrally reviewed; 95 patients were enrolled. DNAm profiles and sequencing were performed on 27 LTS and 24 standard survival GBM (STS). Results: We focused on 73 IDHwt-LTS. All patients underwent at least partial resection, followed by Stupp protocol (48/70). The median time to progression was 43 months (4-186), and almost all received a second treatment. Morphological and routine diagnostic molecular features of LTS did not deviate from the classic findings. MGMT promoter methylation was detected in 92% of cases. No significant differences were observed between LTS and STS in terms of prevalence of mutated genes, with TP53 as the most commonly mutated gene (26% of all samples). DNAm showed a more heterogeneous group for LTS, with several cases classified as pediatric high-grade glioma and peculiar CNVs. We identified 18 differentially methylated regions, 4 associated with survival probability (NR2F2, MME, WDR66 and ENPP4). Methylation levels of individual probes in IGFBP3 gene and corresponding protein expression showed a significant correlation with survival. Conclusions: We found no significant different morphology nor mutational profile of LTS. DNAm confirmed as a valuable tool for GBM classification. No specific episignature was detected, but methylation levels of specific genes had prognostic value in LTS.
2024-03-31 | GSE230770 | GEO
Project description:Multicentric Castleman Disease
| PRJNA1006393 | ENA
Project description:Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening.
2024-12-24 | E-MTAB-13542 | biostudies-arrayexpress
Project description:Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTS) may provide important insight into the biology of GBM. We identified 7 patients with GBM treated at Memorial Sloan-Kettering Cancer Center (MSKCC) with survival greater than 48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTS in two independent cohorts (TCGA and REMBRANDT) and analyzed the transcriptomal characteristics of these LTS. The median overall survival of our cohort was 62.5 months. LTS were distributed between the proneural (n=2), neural (n=2), classical (n=2) and mesenchymal (n=1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identity. The majority of the MSKCC LTS (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutations, and IDH mutation occurred in a minority of the TCGA LTS as well. A set of 42 genes was found to be differentially expressed in the MSKCC and TCGA LTS. While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression.
2014-05-02 | GSE54077 | GEO
Project description:CCG Multicentric Italian Lung Detection
| PRJNA671446 | ENA
Project description:CCG Multicentric Italian Lung Detection
| PRJNA671447 | ENA
Project description:Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTS) may provide important insight into the biology of GBM. We identified 7 patients with GBM treated at Memorial Sloan-Kettering Cancer Center (MSKCC) with survival greater than 48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTS in two independent cohorts (TCGA and REMBRANDT) and analyzed the transcriptomal characteristics of these LTS. The median overall survival of our cohort was 62.5 months. LTS were distributed between the proneural (n=2), neural (n=2), classical (n=2) and mesenchymal (n=1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identity. The majority of the MSKCC LTS (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutations, and IDH mutation occurred in a minority of the TCGA LTS as well. A set of 42 genes was found to be differentially expressed in the MSKCC and TCGA LTS. While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression. All tumors (n = 7) were obtained following surgical resection at the MSKCC as part of routine clinical care, and snap frozen. Tumors were obtained in accordance with Institutional Review Board policies at the MSKCC. Each sample was examined histologically by 3 independent neuropathologists and confirmed to be World Health Organization (WHO) grade IV glioma (GBM). Before analysis, tumors were sectioned and microdissected. Genomic DNA or RNA was extracted using the DNeasy kit (Qiagen) or RNeasy Lipid Tissue Mini Kit (Qiagen) as per the manufacturer’s instructions. Expression analysis of tumors was performed using the Affymetrics U133 2.0 microarray (Affymetrix). Affymetrix CEL files were imported into the Partek Genomics Suite (Partek). The TCGA gene expression data (HT-HG-U133A) was accessed from the TCGA data repositories (http://cancergenome.nih.gov, date of download 12/2013).
2014-05-02 | E-GEOD-54077 | biostudies-arrayexpress
Project description:This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.
| 92735 | ecrin-mdr-crc
Project description:Background: This study aims to find any ambiguous genetic outlier for “oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)” and “astrocytoma, IDH-mutant (A_IDH_mut)” and to redefine the genetic landscape of IDH-mutant gliomas. Methods: The next-generation sequencing (NGS) using a brain tumor-targeted gene panel, methylation profiles, and clinicopathological features were analyzed in O_IDH_mut (n=74) and A_IDH_mut (n=95). Results: Three had ambiguous genetic profiles for O_IDH_mut or A_IDH_mut. Two were unusual TP53-mutant O_IDH_mut, but classified into O_IDH_mut by DKFZ methylation classifier (MC) (score: 0.98). The remaining one was a 1p/19q-codeleted and TERTp-mutant A_IDH_mut, which also had TP53 and CIC mutations. This case matched to O_IDH_mut (Score: 0.75) by the DKFZ-MC v.11b4 algorithm but was corrected to A_IDH_mut_HG (high-grade) (Score: 0.84) using the updated DKFZ-MC v.12.5. The remaining 97.3% and 98.9% of O_IDH_mut and A_IDH_mut had a classic genomic landscape. The patients with MYCN amplified and/or CDKN2A/2B homozygously deleted A_IDH_mut had a worse prognosis than those without these genes alterations Conclusion: CIC and/or FUBP1 mutations were detected in 93.2% and MGMTp methylation were detected in 95.9% of O_IDH_mut patients. Accepting the fact that 1p/19q codeletion and TP53 mutations are not 100% mutually exclusive, as in the three exceptional cases mentioned above, would be of great help in diagnosing the two subtypes of IDH-mutant diffuse glioma. In histopathologically or genetically ambiguous cases, MC can be an objective tool to avoid a diagnosis of NOS (not otherwise specified) or NEC (not elsewhere classified) as well as tumour classification. The authors have not encountered true mixed oligoastrocytomas using genetic and methylation profiles-integrated diagnosis.
2023-03-01 | GSE222423 | GEO