Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

Abstract

Introduction: The emergence of new omics approaches, such as genomic algorithms to identify tumor mutations and molecular modeling tools to predict the three-dimensional structure of proteins, has facilitated the understanding of the dynamic mechanisms involved in the pathogenesis of low-grade gliomas including oligodendrogliomas and astrocytomas. Methods: In this study, we targeted known mutations involved in low-grade gliomas, starting with the sequencing of genomic regions encompassing exon 4 of isocitrate dehydrogenase 1 ( IDH1) and isocitrate dehydrogenase 2 ( IDH2) and the four exons (5-6 and 7-8) of TP53 from 32 samples, followed by computational analysis to study the impact of these mutations on the structure and function of 3 proteins IDH1, IDH2, and p53. Results: We obtain a mutation that has an effect on the catalytic site of the protein IDH1 as R132H and on the catalytic site of the protein IDH2 as R172M. Other mutations at p53 have been identified as K305N, which is a pathogenic mutation; R175 H, which is a benign mutation; and R158G, which disrupts the structural conformation of the tumor suppressor protein. Conclusion: In low-grade gliomas, mutations in IDH1, IDH2, and TP53 may be the key to tumor progression because they have an effect on the function of the protein such as mutations R132H in IDH1 and R172M in IDH2, which change the function of the enzyme alpha-ketoglutarate, or R158G in TP53, which affects the structure of the generated protein, thus their importance in understanding gliomagenesis and for more accurate diagnosis complementary to the anatomical pathology tests.

Novel Driver Strength Index highlights important cancer genes in TCGA PanCanAtlas patients

“…It plays a role in intermediary metabolism and energy production. The most frequent mutations R132 ( IDH1 ) and R172 ( IDH2 ) involve the active site and result in simultaneous loss of normal catalytic activity, the production of α-ketoglutarate, and gain of a new function, the production of 2-hydroxyglutarate (78) (79) (80) (81). 2-hydroxyglutarate is structurally similar to α- ketoglutarate, and acts as an α-ketoglutarate antagonist to competitively inhibit multiple α- ketoglutarate–dependent dioxygenases, including both lysine histone demethylases and the ten-eleven translocation family of DNA hydroxylases (81).…”

Bioinformatics Analysis of Differentially Expressed Genes and miRNAs in Low-Grade Gliomas

“…Low-grade glioma (LGG) is a brain tumor that arises from the glial cells that support and protect the nervous system of the brain; they cause considerable difficulty and represent a therapeutic challenge due to the heterogeneity of their clinical behavior. 1,2 The recent World Health Organization classification of 2016 updated the definition of these tumors to include isocitrate dehydrogenase mutation and 1p / 19q codeletion as an essential biomarker that characterizes gliomas. Indeed, it has become crucial to identify and characterize other candidate glioma biomarkers using bioinformatic analysis, such as genome scanning to detect cancer-specific mutations and the identification of altered epigenetic landscapes in cancer cells or by exploring the differential expression of genes, micro RNAs (miRNAs), and proteins by transcriptomics and proteomics techniques.…”

“…Indeed, it has become crucial to identify and characterize other candidate glioma biomarkers using bioinformatic analysis, such as genome scanning to detect cancer-specific mutations and the identification of altered epigenetic landscapes in cancer cells or by exploring the differential expression of genes, micro RNAs (miRNAs), and proteins by transcriptomics and proteomics techniques. [1][2][3][4]5 Among these high-throughput techniques, RNA sequencing (RNA-seq) is an effective method for robust characterization of the tumor microenvironment. The increasing use of RNA-seq in clinical and scientific contexts offers a powerful opportunity to access new therapeutic biomarkers such as miRNAs which are small noncoding RNAs of approximately 19 to 25 nucleotides in length.…”

“…Low-grade glioma (LGG) is a brain tumor that arises from the glial cells that support and protect the nervous system of the brain; they cause considerable difficulty and represent a therapeutic challenge due to the heterogeneity of their clinical behavior. 1 , 2 …”

“…Indeed, it has become crucial to identify and characterize other candidate glioma biomarkers using bioinformatic analysis, such as genome scanning to detect cancer-specific mutations and the identification of altered epigenetic landscapes in cancer cells or by exploring the differential expression of genes, micro RNAs (miRNAs), and proteins by transcriptomics and proteomics techniques. 1 - 4 , 5…”