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The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory

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Oncology Research 2024年第6期32卷 1037-1045页

作者： maher kurdi ALAA ALKHOTANI ABDULRAHMAN SABBAGH EYAD FAIZO AHMED I.LARY AHMED K.BAMAGA MAJID ALMANSOURI BADR HAFIZ THAMER ALSHARIF SALEH BAEESA Department of Pathology Faculty of MedicineKing Abdulaziz UniversityRabighSaudi Arabia Department of Pathology College of MedicineUmm Al-Qura UniversityMakkahSaudi Arabia Department of Surgery Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Department of Surgery Faculty of MedicineUniversity of TabukTabukSaudi Arabia Section of Neurosurgery Department of SurgeryKing Abdulaziz Medical CityJeddahSaudi Arabia Department of Pediatrics Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Department of Clinical Biochemistry Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Department of Neurosciences King Faisal Specialist Hospital and Research CenterJeddahSaudi Arabia Department of Surgery King Abdulaziz Specialist HospitalTaifSaudi Arabia

Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 *** interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been ***:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype *** groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR ***-cohort statistical significance was ***:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one *** of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated *** IDH-wildtype tumors had unmethylated *** was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer ***:The relationship between PRMT5,MGMT-promoter,and IDH is not ***,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their *** IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 *** alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 ***,using a PRMT5 inhibitor in G4

关键词： Grade 4 astrocytoma Glioblastoma Isocitrate dehydrogenase(IDH) O-6-methylguanine-DNA methyltransferase(MGMT) Protein methyltransferase proteins-5(PRMT5) Progression-free survival(PFS)

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Simple approach for the histomolecular diagnosis of central nervous system gliomas based on 2021 World Health Organization Classification

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World Journal of Clinical Oncology 2022年第7期13卷 567-576页

作者： maher kurdi Rana H Moshref Yousef Katib Eyad Faizo Ahmed A Najjar Basem Bahakeem Ahmed KBamaga Department of Pathology Faculty of MedicineKing Abdulaziz UniversityJeddah 213733Saudi Arabia Department of Neurosciences King Faisal Specialist Hospital and Research CenterJeddah 213733Saudi Arabia Department of Radiology Faculty of MedicineTaibah UniversityAlmadinah Almunawwarah 213733Saudi Arabia Division of Neurosurgery Department of SurgeryFaculty of MedicineTabuk UniversityTabuk 213733Saudi Arabia College of Medicine Taibah UniversityAlmadinah Almunawwarah 213733Saudi Arabia Faculty of Medicine Umm-Alqura UniversityMakkah 213733Saudi Arabia Department of Pediatric Neuromuscular Medicine UnitFaculty of Medicine and King Abdulaziz University HospitalKing Abdulaziz UniversityJeddah 213733Saudi Arabia

The classification of central nervous system(CNS)glioma went through a sequence of developments,between 2006 and 2021,started with only histological approach then has been aided with a major emphasis on molecular signatures in the 4^(th) and 5^(th) editions of the World Health Organization(WHO).The recent reformation in the 5th edition of the WHO classification has focused more on the molecularly defined entities with better characterized natural histories as well as new tumor types and subtypes in the adult and pediatric *** new subclassified entities have been incorporated in the 5^(th) edition after the continuous exploration of new genomic,epigenomic and transcriptomic ***,the current guidelines of 2021 WHO classification of CNS tumors and European Association of Neuro-Oncology(EANO)exploited the molecular signatures in the diagnostic approach of CNS *** current review presents a practical diagnostic approach for diffuse CNS gliomas and circumscribed astrocytomas using histomolecular criteria adopted by the recent WHO *** also describe the treatment strategies for these tumors based on EANO guidelines.

关键词： Central Nervous System glioma Classification World Health Organization 2021 European Association of Neuro-Oncology guidelines

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Immune microenvironment of medulloblastoma:The association between its molecular subgroups and potential targeted immunotherapeutic receptors

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World Journal of Clinical Oncology 2023年第3期14卷 117-130页

作者： maher kurdi Nasser Mulla Husam Malibary Ahmed K Bamaga Motaz M Fadul Eyad Faizo Sahar Hakamy Saleh Baeesa Department of Pathology Faculty of MedicineKing Abdulaziz UniversityRabigh 213733Saudi Arabia Neuromuscular Unit King Fahad Medical Research CenterKing Abdulaziz UniversityJeddah 213733Saudi Arabia Department of Internal Medicine Faculty of MedicineTaibah UniversityMedina 213733Saudi Arabia Department of Internal Medicine Faculty of MedicineKing Abdulaziz UniversityJeddah 213733Saudi Arabia Department of Paediatrics Faculty of MedicineKing Abdulaziz UniversityJeddah 213733Saudi Arabia Division of Neurosurgery Department of SurgeryFaculty of MedicineTabuk UniversityTabuk 213733Saudi Arabia Neurmuscular Unit Center of Excellence of Genomic MedicineJeddah 21423Saudi Arabia Department of Neuroscience King Faisal Specialist Hospital and Research CenterJeddahSaudi Arabia

Medulloblastoma(MB)is considered the commonest malignant brain tumor in *** treatments consisting of surgery,radiation,and chemotherapy have improved patients’***,the recurrence occurs in 30%of *** persistent mortality rates,the failure of current therapies to extend life expectancy,and the serious complications of non-targeted cytotoxic treatment indicate the need for more refined therapeutic *** MBs originating from the neurons of external granular layer line the outer surface of neocerebellum and responsible for the afferent and efferent ***,MBs have been segregated into four molecular subgroups:Wingless-activated(WNT-MB)(Group 1);Sonichedgehog-activated(SHH-MB)(Group 2);Group 3 and 4 *** molecular alterations follow specific gene mutations and disease-risk *** current treatment protocols and ongoing clinical trials against these molecular subgroups are still using common chemotherapeutic agents by which their efficacy have improved the progression-free survival but did not change the overall ***,the need to explore new therapies targeting specific receptors in MB microenvironment became *** immune microenvironment of MBs consists of distinctive cellular heterogeneities including immune cells and none-immune *** associate macrophage and tumour infiltrating lymphocyte are considered the main principal cells in tumour microenvironment,and their role are still under *** this review,we discuss the mechanism of interaction between MB cells and immune cells in the microenvironment,with an overview of the recent investigations and clinical trials.

关键词： Medulloblastoma Tumour microenvironment Tumour associated macrophages Tumour infiltrating lymphocyte Immunotherapies

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