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Protein Arginine Methyltransferase 5 (PRMT5) is an enzyme that regulates gene expression and protein function through arginine methylation. Its association with isocitrate dehydrogenase (IDH) mutation in Grade-4 astrocytoma was rarely investigated. Our aim was to aim to explore the association between IDH mutation and PRMT5 and its effect on tumor recurrence. A retrospective cohort of 34 patients with Grade 4 astrocytoma has been tested for PRMT5 expression using protein and gene expression arrays. The impact of IDH-mutation and PRMT5 expression on tumor recurrence was explored. IDH-wildtype was detected in 13 tumors. PRMT5 protein was highly expressed in 30 tumors and the expression was low in four tumors. PRMT5 gene expression was upregulated in 33 tumors and downregulated in a single tumor case. Tumors with different PRMT5 gene expressions and IDH mutation were found to have a significant statistical difference in recurrence-free interval (RFI) (p-value<0.001). IDH-wildtype glioblastoma with upregulated PRMT5 gene or protein expression showed earlier tumor recurrence compared to IDH-mutant Grade 4 astrocytoma with upregulated PRMT5 expression. The association between IDH mutation and PRMT5 in IDH-mutant Grade 4 astrocytoma or IDH-wildtype glioblastoma is indirectly bidirectional. PRMT5 upregulation in glioblastoma can lead to increased cell proliferation and tumor regrowth. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid-2-related factor 2 (NRF2), a transcriptional gene factor related to nuclear factor erythroid 2, plays a role in the development of gliomas with isocitrate dehydrogenase (IDH) mutation. Its impact on tumour recurrence has seldom been investigated. A group of 34 patients diagnosed with Grade 4 astrocytoma was included in a retrospective cohort. NRF2 protein and gene expressions were assessed using different profiling assays. The association between IDH mutation, NRF2 expression, and tumor recurrence was investigated. The mean patients' age in this study was 50 years. Out of the total number of tumors analyzed, 21 of them had IDH mutation. NRF2 protein expression was found to be overexpressed in 27 tumors and reduced in 7 tumors. Additionally, NRF2 gene was upregulated in 24 tumors and downregulated in 10 tumors. Insignificant statistical difference was observed in recurrence-free interval (RFI) between patients with upregulated or downregulated NRF2 gene or protein expressions (p-value>0.05). However, this relationship is distinctive when NRF2 expression was compared to IDH mutation. Tumors with different levels of NRF2 expressions and IDH mutations showed significant statistical variation in RFI (p-value=0.001). There was insignificant impact on RFI among patients receiving different chemotherapies (TMZ or TMZ plus) who had abnormal NRF2 gene activities (p-value=0.97). WHO-Grade 4 astrocytoma with IDH mutation and altered NRF2 expression showed a delayed tumor recurrence compared to IDH-wildtype glioblastoma. [ABSTRACT FROM AUTHOR]

aimi,7,8 Ghadeer Alrefaei,9 Nouf Alsubhi,10 Aziza Alrafiah,7 Safiah Alhazmi1,31Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Biology, King Khalid University, Abha, Saudi Arabia; 3Princess Dr. Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Internal Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 5Medical Reference Clinics, Jeddah, Saudi Arabia; 6Hematology Research Unit (HRU), King Fahad Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 7Department of Medical Laboratory Science, King Abdulaziz University, Jeddah, Saudi Arabia; 8Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; 9Department of Biology, University of Jeddah, Jeddah, Saudi Arabia; 10Biological Sciences Department, College of Science & Arts, King Abdulaziz University, Rabigh, Saudi Arabia*These authors contributed equally to this workCorrespondence: Aziza Alrafiah, Tel +966‐126401000 (ext. 23495), Fax +966‐126401000 (Ext. 21686), Email [email protected] Background: Breast cancer is one of the most common malignancies among women. Recent studies revealed that differentially methylated regions (DMRs) are implicated in regulating gene expression. The goal of this research was to determine which genes and pathways are dysregulated in breast cancer when their promoters are methylated in an abnormal way, leading to differential expression. Whole-genome bisulfite sequencing was applied to analyze DMRs for eight peripheral blood samples collected from five Saudi females diagnosed with stages I and II of breast cancer aligned with three normal females. Three of those patients and three normal samples were used to determine differentially expressed genes (DEG) using Illumina platform NovaSeq PE150.Results: Based on ontology (GO) and KEGG pathways, the analysis indicated that DMGs and DEG are closely related to associated processes, such as ubiquitin-protein transferase activity, ubiquitin-mediated proteolysis, and oxidative phosphorylation. The findings indicated a potentially significant association between global hypomethylation and breast cancer in Saudi patients. Our results revealed 81 differentially promoter-methylated and expressed genes. The most significant differentially methylated and expressed genes found in gene ontology (GO) are pumilio RNA binding family member 1 (PUM1) and zinc finger AN1-type containing 2B (ZFAND2B) also known as (AIRAPL).Conclusion: The essential outcomes of this study suggested that aberrant hypermethylation at crucial genes that have significant parts in the molecular pathways of breast cancer could be used as a potential prognostic biomarker for breast cancer. [ABSTRACT FROM AUTHOR]

NDRG2 is a tumour suppressor gene involved in tumor growth inhibition. Its effect on tumour recurrence remains controversial. The aim of this study is to explore the dual effect of IDH mutation and NDRG2 dysregulation in WHO-Grade 4 astrocytoma recurrence. A group of 36 patients with WHO-Grade 4 astrocytoma were examined for NDRG2 expression using protein and gene expression assays. The relationship between IDH, NDRG2 protein and gene expressions, and recurrence-free interval [RFI] was explored. The mean patients age in this study was 45-years with 21 males and 15 females. IDH was mutant in 22 tumors. NDRG2 protein expression was low in 23 tumors, and high in 13 tumors. NDRG2 gene expression was upregulated in 4 tumors and 32 tumors showed NDRG2 gene downregulation. The consistency between two tasting methods of NDRG2 expression was 52.8%. There was a significant statistical difference in RFI among tumors with varying NDRG2 gene expression and IDH mutation [p-value= 0.021]. IDH-mutant tumours with downregulated NDRG2 expression showed late recurrence compared to IDH-wildtype glioblastoma. IDH-mutant WHO Grade-4 astrocytoma with downregulated NDRG2 gene are associated with late tumor recurrence. IDH mutations cause excessive accumulation of D-2-hydroxyglutarate, that may inhibit the activity of TET proteins, potentially leading to DNA hypermethylation and gene silencing. [ABSTRACT FROM AUTHOR]

Tumor suppressor (p53) acts to integrate multiple stress signals into diverse antiproliferative responses. Its potential to transactivate or downregulate genes through apoptotic pathway in IDH-wildtype glioblastoma has never been explored. A group of twenty patients diagnosed with IDH-wildtype glioblastoma, were tested for p53 expression and NDRG2/NRF2 genes activity through protein and gene profiling assays. The connotation between these elements has been explored. The mean patients' age was 64-years. All tumors were IDH-wildtype. p53 was expressed in 12 tumors and absent in 8 tumors. The activity of NDRG2 gene was downregulated in all cases. The activity of NRF2 gene was upregulated in 17 tumors and downregulated in 3 tumors. There was a significant statistical difference in PFS among tumors exhibiting different levels of p53 expression and NDRG2 gene activity [p-value= 0.025], in which 12 tumors with downregulated NDRG2 expression and positive p53 expression had earlier tumor recurrence. This statistical difference in PFS was insignificant when we compared p53 expression with NRF2 gene activity [p-value= 0.079]. During cell cycle arrest at G2 phase, p53 expression in IDH-wildtype glioblastoma in elderly individuals, coupled with the downregulation of NDRG2 gene activity, led to an aberrant increase in tumor cell proliferation and accelerated tumor recurrence. However, the influence of p53 on NRF2 gene activity was found to be insignificant. [ABSTRACT FROM AUTHOR]

MHC-I expression is a crucial factor in cancer immunity, and its regulations can impact tumor progression and recurrence. The mechanism through which glioblastoma use MHC-I to avoid immunosurveillance has been rarely investigated. A retrospective cohort of 35 patients with IDH-mutant WHO-Grade 4 astrocytoma and IDH-wildtype glioblastoma were examined for MHC-I using protein and gene expression assays. The association between IDH mutation, TP53 mutation, and MHC-I expression with recurrence-free interval were investigated. The average patients' age was 49.6 year. IDH was wildtype in 13 tumors. MHC-I protein expression was absent in 30 tumors, faint in 4 tumors, and membrane bound dense expression in single tumor. MHC-I expression was upregulated in 10 tumors and 25 tumors showed MHC-I downregulation. P53 was positively expressed in 19 cases and lost in 13 cases. A significant statistical difference was observed in the RFI between tumors with distinct MHC-I expression and IDH-mutation [p-value = 0.008]. IDH-wildtype tumors with upregulated MHC-I expression showed late tumor recurrence compared to IDH-wildtype tumors with downregulated MHC-I expression. There was insignificant statistical difference in RFI among patients with varying degree of MHC-I expression, who received TMZ or TMZ and other chemotherapies [P-value = 0.44] Glioblastoma with upregulated MHC-I showed a delayed tumor recurrence in comparison to those with downregulated MHC-I expression. However, downregulated MHC-I may not necessarily be an indicator of poor problems. [ABSTRACT FROM AUTHOR]