Impact of CDKN2A/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma

Huang, L. Eric

doi:10.3390/biomedicines10020246

Cited by 25 publications

(25 citation statements)

References 53 publications

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“…One of the major criteria to distinguish WHO_Grade4_ Astrocytomas _IDH1 mut from WHO_Grade2_ and WHO_Grade3_Astrocytomas _IDH1 mut is patients belong to WHO_Grade4_Astrocytomas harbored CDKN2A/B homozygous deletion. Functionally, CDKN2A/B serve as CDK4/6 inhibitors 47 , we then tried to illustrate whether this genomic-alteration contributed to the cell proliferation features of WHO_Grade4_Astrocytomas _IDH1 mut . Based on this hypothesis, we examined the multi-gene proliferation score (MGPS) between Astrocytoma samples with and without CDKN2A/B homozygous deletion, and found Astrocytoma samples with CDKN2A/B homozygous deletion showed elevated MGPSs, suggesting their fast proliferation feature (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms

et al. 2023

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Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein: PD-L1 and CD70 in T-cell infiltrated tumors.

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Section: Resultsmentioning

confidence: 99%

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms

et al. 2023

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“…Updates to the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and the 2021 fifth edition of the WHO classification of CNS tumors have been published 63 . Increasing numbers of genetic alterations are being included to classify or grade DGs more precisely 64 , 65 . The entity of GBM-IDHm was substituted by a novel subtype of astrocytoma, CNS WHO grade 4.…”

Section: Discussionmentioning

confidence: 99%

Clinical management and survival outcomes of patients with different molecular subtypes of diffuse gliomas in China (2011–2017): a multicenter retrospective study from CGGA

Zhang

Liu

et al. 2022

Cancer Biol Med

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Objective: We aimed to summarize the clinicopathological characteristics and prognostic features of various molecular subtypes of diffuse gliomas (DGs) in the Chinese population. Methods: In total, 1,418 patients diagnosed with DG between 2011 and 2017 were classified into 5 molecular subtypes according to the 2016 WHO classification of central nervous system tumors. The IDH mutation status was determined by immunohistochemistry and/or DNA sequencing, and 1p/19q codeletion was detected with fluorescence in situ hybridization. The median clinical follow-up time was 1,076 days. T-tests and chi-square tests were used to compare clinicopathological characteristics. Kaplan-Meier and Cox regression methods were used to evaluate prognostic factors. Results: Our cohort included 15.5% lower-grade gliomas, IDH-mutant and 1p/19q-codeleted (LGG-IDHm-1p/19q); 18.1% lower-grade gliomas, IDH-mutant (LGG-IDHm); 13.1% lower-grade gliomas, IDH-wildtype (LGG-IDHwt); 36.1% glioblastoma, IDH-wildtype (GBM-IDHwt); and 17.2% glioblastoma, IDH-mutant (GBM-IDHm). Approximately 63.3% of the enrolled primary gliomas, and the median overall survival times for LGG-IDHm, LGG-IDHwt, GBM-IDHwt, and GBM-IDHm subtypes were 75.97, 34.47, 11.57, and 15.17 months, respectively. The 5-year survival rate of LGG-IDHm-1p/19q was 76.54%. We observed a significant association between high resection rate and favorable survival outcomes across all subtypes of primary tumors. We also observed a significant role of chemotherapy in prolonging overall survival for GBM-IDHwt and GBM-IDHm, and in prolonging post-relapse survival for the 2 recurrent GBM subtypes. Conclusions: By controlling for molecular subtypes, we found that resection rate and chemotherapy were 2 prognostic factors associated with survival outcomes in a Chinese cohort with DG.

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“…The CDKN2A gene is located on chromosome 9p21.3. It has a role in the coding of two oncosuppressor proteins, p53 and pRB [ 38 ]. In grade 4 gliomas, the incidence of its mutation can be found in up to 70% of cases, and its absence leads to the activation of the gliomagenesis process by activating the Rb1 pathway [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Aggressiveness of Grade 4 Gliomas of Adults

Deacu

Axelerad

Popescu

et al. 2022

Clinics and Practice

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Grade 4 adult gliomas are IDH-mutant astrocytomas and IDH-wildtype glioblastomas. They have a very high mortality rate, with survival at 5 years not exceeding 5%. We aimed to conduct a clinical imaging and morphogenetic characterization of them, as well as to identify the main negative prognostic factors that give them such aggressiveness. We conducted a ten-year retrospective study. We followed the clinical, imaging, and morphogenetic aspects of the cases. We analyzed immunohistochemical markers (IDH1, Ki-67, and nestin) and FISH tests based on the CDKN2A gene. The obtained results were analyzed using SPSS Statistics with the appropriate parameters. The clinical aspects representing negative prognostic factors were represented by patients’ comorbidities: hypertension (HR = 1.776) and diabetes mellitus/hyperglycemia (HR = 2.159). The lesions were mostly supratentorial, and the temporal lobe was the most affected. The mean volume was 88.05 cm3 and produced a midline shift with an average of 8.52 mm. Subtotal surgical resection was a negative prognostic factor (HR = 1.877). The proliferative index did not influence survival rate, whereas CDKN2A gene mutations were shown to have a major impact on survival. We identified the main negative prognostic factors that support the aggressiveness of grade 4 gliomas: patient comorbidities, type of surgical resection, degree of cell differentiation, and CDKN2A gene mutations.

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Impact of CDKN2A/B Homozygous Deletion on the Prognosis and Biology of IDH-Mutant Glioma

Cited by 25 publications

References 53 publications

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms

Clinical management and survival outcomes of patients with different molecular subtypes of diffuse gliomas in China (2011–2017): a multicenter retrospective study from CGGA

Aggressiveness of Grade 4 Gliomas of Adults

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