Gliomas are the most common type of human brain cancers and make up a third of all tumours of the central nervous system. Mutations in the IDH-gene are frequent and regarded as an early event in gliomagenesis. IDH mutations are considered to be associated with better outcome. If this accounts for all histological subtypes and for low as well as for high grade gliomas has yet to be clarified. The aim of this paper is to present recent evidence on the question of whether mutations of the IDH-gene affect the outcome of patients with glioma/glioblastoma.
For this, electronic databases were searched for studies published after 2008, which yielded 1160 articles. The quality of the studies was critically evaluated. Overall Survival, Progression Free Survival and their p-values were analysed to assess the relation between IDH mutation and outcome. The results were extracted, analysed and compared to gain a thorough overview of the current evidence base.
Table of Contents
Introduction
Definition Gliomas and Glioblastomas
Isocitratdehydrogenase- Gene & the Enzyme IDH
Epidemiology and Prognosis
Cell of origin, Epigenetics & Genetic Pathways of Tumorigenesis
Treatment Implications of IDH
Indications for a Systematic Review
Aims
Methodology
Research Question
Databases
Search strategy
Study Selection
Eligibility criteria
Inclusion criteria
Exclusion criteria
Study Analysis/ Quality Assessment
Results
Search results
Study and participant characteristics
Analysis of Data & Discussion
Conclusion
Objectives & Core Themes
This systematic review investigates whether mutations in the IDH gene influence the clinical outcome and therapy response of patients diagnosed with various grades of glioma and glioblastoma. By consolidating evidence from multiple cohort studies, the work seeks to clarify if IDH mutation status serves as a reliable prognostic factor and how it correlates with progression-free and overall survival.
- Prognostic impact of IDH mutations on glioma patients
- Differentiation between WHO grades II, III, and IV in terms of IDH mutation effects
- Clinical efficacy of therapy based on IDH mutation status
- Role of molecular markers (TP53, 1p/19q co-deletion) in tumor prognosis
- Synthesis of evidence for current and future clinical guidelines
Excerpt from the publication
ISOCITRATDEHYDROGENASE- GENE & THE ENZYME IDH
The wildtype IDH gene codes for the enzyme IDH, responsible for catalysing the oxidative decarboxylation of isocitrate into alpha-ketoglutarate (α-KG) under concomitant production of NADPH. IDH1 is located within the cytoplasm and peroxisomes whereas IDH2 is found in mitochondria. The activity of IDH makes up about two-thirds of the NADPH production in the brain. Among other functions, NADPH is critically important in reducing glutathione and thioredoxin to prevent oxidative stress in the tissues. It is the main antioxidant of the body.
Alpha-KG is an important substrate in the Kreb’s cycle, and thus in the body’s energy metabolism. Alpha-KG can be transaminated to glutamate and stands in a delicate equilibrium with this physiologically important amino acid. Glutamate plays a crucial role in the physiology of glial cells. Hence, a disruption of this balance is thought to contribute to formation of malignant gliomas.
If needed, IDH catalyses the reverse reaction as well: conversion of alpha-ketoglutarate into isocitrate which can be further converted to acetyl-CoA -a major substrate for multiple biochemical reactions all over the body.
NADPH scavenges oxygen radicals and is especially important in the brain as it is the organ being least capable of tolerating oxidative stress. IDH mutations reduce the brain’s capacity to produce NADPH by about 40% and hence the brains capacity to tolerate oxidative stress.
Summary of Chapters
Introduction: Provides the foundational definitions of gliomas and glioblastomas, explaining the significance of IDH mutations and their role in cell metabolism and tumorigenesis.
Aims: Outlines the core research questions focusing on the prognostic value of IDH mutation status in relation to overall and progression-free survival.
Methodology: Details the systematic search strategy across major databases and establishes the inclusion/exclusion criteria used to select 23 high-quality cohort studies.
Results: Presents the consolidated findings from 4356 patients, highlighting the prevalence of IDH mutations and their correlation with tumor grades and subtypes.
Analysis of Data & Discussion: Examines the evidence regarding therapeutic responses and survival benefits, addressing the heterogeneity of results across different WHO grades.
Conclusion: Summarizes that while IDH mutations consistently indicate a more favorable prognosis in high-grade gliomas, their predictive value in low-grade gliomas is more complex and subtype-dependent.
Key Words
Glioma, Glioblastoma, IDH mutation, Isocitrate dehydrogenase, Overall survival, Progression-free survival, WHO classification, Neuropathology, Tumorigenesis, Prognostic marker, Molecular markers, 1p/19q co-deletion, TP53.
Frequently Asked Questions
What is the primary focus of this research paper?
This paper is a systematic review that examines the relationship between IDH gene mutations and the clinical outcomes of patients diagnosed with gliomas and glioblastomas.
What are the central themes discussed in the work?
The work covers tumor genetics, the impact of IDH mutations on cellular metabolism, prognostic outcomes, and the varying responses to standard therapies like chemotherapy and radiotherapy.
What is the main goal or research question?
The study aims to determine if patients with IDH-mutant gliomas show better overall survival (OS) and progression-free survival (PFS) compared to those with IDH-wildtype tumors.
Which scientific methodology was utilized?
The author conducted a systematic review, searching multiple electronic databases (MEDLINE, Embase, Cochrane) for studies published after 2008, followed by critical appraisal using the CASP framework and the Newcastle-Ottawa Scale.
What topics are covered in the main body of the text?
The main body covers the definition and classification of gliomas, the biochemical function of IDH enzymes, the impact of mutations on tumorigenesis, and an analysis of clinical evidence regarding patient survival.
Which keywords best describe this research?
Key terms include Glioma, Glioblastoma, IDH mutation, Overall Survival, Progression-Free Survival, and molecular prognostic markers.
Why are results regarding WHO grade II gliomas considered heterogeneous?
Results for grade II gliomas are considered controversial and diverse because the studies include varying proportions of histological subtypes (oligodendrogliomas vs. astrocytomas) which respond differently to treatment.
What is the significance of the "neomorphic activity" of the mutant IDH enzyme?
The mutation leads to the overproduction of the oncometabolite 2HG, which competitively inhibits enzymes and causes DNA hypermethylation, acting as a major driver of gliomagenesis.
How does the 1p/19q co-deletion affect the prognosis of IDH-mutant gliomas?
The paper notes that the 1p/19q co-deletion is a well-established marker for a positive clinical outcome, frequently associated with oligodendrogliomas, leading to a better prognosis compared to non-deleted tumors.
- Quote paper
- Ronja Handwerker (Author), 2018, Review of therapy response and survival of patients with glioma or glioblastoma and IDH mutation, Munich, GRIN Verlag, https://www.grin.com/document/465476
