Using the molecular classification of glioblastoma to inform personalized treatment

Abstract

Glioblastoma is the most common and most aggressive diffuse glioma, associated with short survival and uniformly fatal outcome, irrespective of treatment. It is characterized by morphological, genetic and gene-expression heterogeneity. The current standard of treatment is maximal surgical resection, followed by radiation, with concurrent and adjuvant chemotherapy. Due to the heterogeneity, most tumours develop resistance to treatment and shortly recur. Following recurrence, glioblastoma is quickly fatal in the majority of cases. Recent genetic molecular advances have contributed to a better understanding of glioblastoma pathophysiology and disease stratification. In this paper we review basic glioblastoma pathophysiology, with emphasis on clinically relevant genetic molecular alterations and potential targets for further drug development.

Keywords: 1p/19q; EGFR; FGFR; IDH; MGMT; TACC; glioblastoma; mesenchymal; pathogenesis; proneural.

Conflict of interest statement

Conflict of interest: The authors report no conflict of interest.

Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Figures

Fig. 1

Left upper: H&E stained cortical section of glioblastoma. Right upper: IDH1 R132H immunostain highlights the neoplastic cells. Lower images: Numerous IDH1 R132H positive neoplastic cells infiltrate the neuropil at a distance from the main tumor focus.

Fig. 2

Histopathology of glioblastoma: H&E, intermediate power – proliferating atypical cells with mitotic activity, necrosis with pseudopalisading (left), and microvascular proliferation (right).

Fig. 3

Gene expression profiling defines three major tumor subsets: proneural (PN), mesenchymal (Mes), and proliferative (Prolif) – from Philips et al [2] 2006 with permission.

Fig. 4

Hierarchical unsupervised clustering of TCGA Glioblastoma by methylation status. Each row represents a probe; each column represents a sample. The level of DNA methylation is represented with a color scale as shown in the key; white indicates missing data. Legend: M.SssI - CpG Methyltransferase treated DNA; WGA – whole genome amplified DNA. From Noushmehr et al, 2010 [63] with permission.

Fig. 5

G-CIMP prevalence and outcome in diffuse glioma: left – Methylation profiling shows an association of CIMP status with tumor grade (red = methylated; green = unmethylated; black line = G-CIMP/IDH1 positive; gray line = G-CIMP/IDH1 negative; white lines = unknown IDH status); right – Kaplan-Meier survival curves plotting patient outcome by G-CIMP status (red lines = G-CIMP positive; black lines = G-CIMP negative). From Noushmehr et al, 2010 [63] with permission.