Molecular heterogeneity in glioblastoma: potential clinical implications

Abstract

Glioblastomas, (grade 4 astrocytomas), are aggressive primary brain tumors characterized by histopathological heterogeneity. High-resolution sequencing technologies have shown that these tumors also feature significant inter-tumoral molecular heterogeneity. Molecular subtyping of these tumors has revealed several predictive and prognostic biomarkers. However, intra-tumoral heterogeneity may undermine the use of single biopsy analysis for determining tumor genotype and has implications for potential targeted therapies. The clinical relevance and theories of tumoral molecular heterogeneity in glioblastoma are discussed.

Keywords: biomarkers; glioblastoma; glioma; heterogeneity; intra-tumoral heterogeneity; molecular; transcriptional subtype.

Figure 1

Molecular classification of major glioblastoma subtypes and correlation with treatment response and outcome. IDH1/2 mutations are major prognostic biomarkers, stratifying primary and secondary pathways of gliomagenesis. Primary glioblastoma features a high frequency of TERT mutations, whereas IDH1/2 mutated glioma (including secondary glioblastoma and low grade glioma) may be further subdivided on the basis of co-mutations in either ATRX and TP53 or CIC and FUBP1, occurring at high frequency in astrocytic or oligodendroglial tumor subtypes. Co-deletion of 1p and 19q, a marker of enhanced chemosensitivity, also clusters with mutations in CIC and FUBP1. Primary glioblastomas display classical, mesenchymal, and neural phenotypes, whereas secondary glioblastomas tend to display a proneural phenotype that shifts toward a mesenchymal phenotype with recurrence. The significantly improved outcome of the proneural subset is due to the G-CIMP phenotype, established by IDH1/2-mediated metabolic reprogramming of the epigenome. Primary glioblastomas and a subset of proneural tumors are glioma-CpG island hypermethylator phenotype (G-CIMP) negative, and a large proportion are MGMT unmethylated. Both classical and mesenchymal transcriptional subtypes benefit from concurrent chemoradiotherapy, however, MGMT status is only predictive of treatment response in the classical subset.

Figure 2

Glioblastoma tumor heterogeneity and implications for patient management. Tumor evolution and tumor heterogeneity may be promoted by clonal evolution, cancer stem cells and interclonal cooperativity. (A) According to the theory of clonal evolution, somatic alterations affecting the initial cell of origin give rise to multiple cancer clones, with different sensitivity to therapy and ability to survive and proliferate. These tumor cell clones are genetically unstable, undergoing successive waves of genetic alterations, and clones with the most aggressive phenotype are favored. For example, only the MGMT methylated cells sensitive to temozolomide (TMZ) disappear following TMZ treatment. (B) In contrast, according to the cancer stem cell theory, only a single subset of cells, known as cancer stem cells (CSC), possess the ability to self-renew, continuously proliferate and give rise to clones of variable genetic profiles, and are inherently resistant to therapy. (C) The theory of interclonal cooperativity suggests that tumor evolution and heterogeneity is promoted by interactions between tumor cell clones and their microenvironment, with immune/stromal factors influencing malignant progression. Significant clonal diversity within tumor specimens may explain the failure of molecularly targeted therapies in glioblastoma patients.