Predictive and Prognostic Factors for Gliomas
Predictive and Prognostic Factors for Gliomas
Despite recent therapeutic advances, gliomas, in particular the most frequent and malignant glioblastoma, remain devastating tumors and need a better molecular characterization to improve both classification and treatment. Currently, three molecular markers, related to better outcome, are particularly useful and complement the histological classification: the 1p/19q codeletion strongly predicts prolonged response to treatment and prolonged survival in oligodendroglial tumors; the O-methylguanine-DNA methyltransferase promoter methylation, which is hypothesized to render the cell more vulnerable to alkylants, is associated with a stronger benefit of concomitant chemoradiotherapy in glioblastomas; mutations of the IDH1 (more rarely IDH2) gene affects 40% of gliomas (but 100% of the 1p/19q codeleted gliomas) and is inversely correlated to grade. IDH1 mutation is a strong and independent predictor of survival, whatever grade considered. The consequences of IDH1/IDH2 mutation (that results in a new enzymatic activity transforming alphacetoglutarate into 2-hydroxyglutarate) are currently under investigation. Recently, integrated genomic, transcriptomic and epigenetic studies have unraveled new glioblastoma subgroups that further refines the molecular classification of these tumors. Such an approach should be extended to lower grade gliomas.
Despite recent advances in glioma treatment, patient outcome remains dismal, with a median overall survival of approximately 15 months for patients suffering from the most aggressive subtype, glioblastoma (grade IV). The WHO classifies gliomas according to morphological features as astrocytic (grade I–IV), oligodendroglial (grade II and III) or mixed tumors (grade II and III). Grading is based on cellularity, mitotic activity, nuclear atypia, vascularity and necrosis. Glioblastoma is characterized by the presence of areas of vascular proliferation and/or necrosis. Most frequently, glioblastoma appears de novo (primary glioblastoma), but may also arise from lower grade astrocytoma, oligoastrocytoma (or mixed glioma), as well as oligodendroglioma, when it is termed 'secondary' glioblastoma. This classification system remains unsatisfactory owing to its lack of reproducibility – giving rise to a high rate of inter- and even intra-observer discrepancies – and to its lack of precision in terms of prognosis. These limitations are related to the fact that classification is still based on subjective criteria – both for phenotype determination and grading – and the fact that one histological subtype encompasses different molecular subtypes with different prognoses. Indeed, it is becoming increasingly clear that tumors that share identical histopathologic features can actually represent multiple distinct molecular phenotypes. A more detailed molecular understanding of these tumors is thus crucial to improve classification, to better predict outcome, to better stratify patients included in clinical trials and, finally, to tailor specific treatments to individual tumor types or patients. To date, three biomarkers – codeletion of chromosomes 1p and 19q, O-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and mutations in the isocitrate dehydrogenase (IDH) IDH1/IDH2 genes – have been identified as potent prognostic factors in gliomas. More recently, integrated genomic, transcriptomic and epigenetic studies have identified new molecular subgroups of gliomas that further refine the molecular classification of glioblastomas.
Abstract and Introduction
Abstract
Despite recent therapeutic advances, gliomas, in particular the most frequent and malignant glioblastoma, remain devastating tumors and need a better molecular characterization to improve both classification and treatment. Currently, three molecular markers, related to better outcome, are particularly useful and complement the histological classification: the 1p/19q codeletion strongly predicts prolonged response to treatment and prolonged survival in oligodendroglial tumors; the O-methylguanine-DNA methyltransferase promoter methylation, which is hypothesized to render the cell more vulnerable to alkylants, is associated with a stronger benefit of concomitant chemoradiotherapy in glioblastomas; mutations of the IDH1 (more rarely IDH2) gene affects 40% of gliomas (but 100% of the 1p/19q codeleted gliomas) and is inversely correlated to grade. IDH1 mutation is a strong and independent predictor of survival, whatever grade considered. The consequences of IDH1/IDH2 mutation (that results in a new enzymatic activity transforming alphacetoglutarate into 2-hydroxyglutarate) are currently under investigation. Recently, integrated genomic, transcriptomic and epigenetic studies have unraveled new glioblastoma subgroups that further refines the molecular classification of these tumors. Such an approach should be extended to lower grade gliomas.
Introduction
Despite recent advances in glioma treatment, patient outcome remains dismal, with a median overall survival of approximately 15 months for patients suffering from the most aggressive subtype, glioblastoma (grade IV). The WHO classifies gliomas according to morphological features as astrocytic (grade I–IV), oligodendroglial (grade II and III) or mixed tumors (grade II and III). Grading is based on cellularity, mitotic activity, nuclear atypia, vascularity and necrosis. Glioblastoma is characterized by the presence of areas of vascular proliferation and/or necrosis. Most frequently, glioblastoma appears de novo (primary glioblastoma), but may also arise from lower grade astrocytoma, oligoastrocytoma (or mixed glioma), as well as oligodendroglioma, when it is termed 'secondary' glioblastoma. This classification system remains unsatisfactory owing to its lack of reproducibility – giving rise to a high rate of inter- and even intra-observer discrepancies – and to its lack of precision in terms of prognosis. These limitations are related to the fact that classification is still based on subjective criteria – both for phenotype determination and grading – and the fact that one histological subtype encompasses different molecular subtypes with different prognoses. Indeed, it is becoming increasingly clear that tumors that share identical histopathologic features can actually represent multiple distinct molecular phenotypes. A more detailed molecular understanding of these tumors is thus crucial to improve classification, to better predict outcome, to better stratify patients included in clinical trials and, finally, to tailor specific treatments to individual tumor types or patients. To date, three biomarkers – codeletion of chromosomes 1p and 19q, O-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and mutations in the isocitrate dehydrogenase (IDH) IDH1/IDH2 genes – have been identified as potent prognostic factors in gliomas. More recently, integrated genomic, transcriptomic and epigenetic studies have identified new molecular subgroups of gliomas that further refine the molecular classification of glioblastomas.
Source...