Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment.

Annette B Håvik,Torstein R Meling,Ragnhild A Lothe,Lina Cekaite,Sverre Heim,Guro E Lind,David Scheie,Petter Brandal,Marine Jeanmougin,Trude H Ågesen,Anita Sveen

doi:10.1002/1878-0261.12668

Annette B Håvik, Torstein R Meling + Show 9 more

Open Access

https://doi.org/10.1002/1878-0261.12668

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Abstract

Glioblastoma (GBM), the most aggressive form of brain cancer, is characterized by a high level of molecular heterogeneity, and infiltration by various immune and stromal cell populations. Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. We have investigated the abundance of infiltrating immune and stromal cells in silico, from gene expression profiles. Two cohorts, including in‐house normal brain and glioma samples (n = 70) and a large sample set from TCGA (n = 393), were combined into a single exploratory dataset. A third independent cohort (n = 124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. We identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes with improving prognostic models in GBM.

Highlights

Gliomas account for 25% of all primary central nervous system tumors in adults (Ostrom et al, 2016)
In silico analyses of individual immune and stromal cell populations in the exploratory dataset underlined a higher variability in the composition of the microenvironment of primary GBMs (pGBM) compared to grade II astrocytoma (AII) and other subtypes (Fig. 1A)
Further differential analyses established that the pGBM-I1 cluster had significant increased infiltration in nine out of ten cell populations (B lineage, CD8 T cells, endothelial cells, fibroblasts, monocytic lineage and myeloid dendritic cells, neutrophils, natural killer (NK) cells, and T cells; Fig. 1B)

Summary

Introduction

Gliomas account for 25% of all primary central nervous system tumors in adults (Ostrom et al, 2016). The World Health Organization (WHO) grading system classifies gliomas into grades I–IV based on histopathological features (Louis et al, 2016). Glioblastomas (GBMs, grade IV gliomas) are the most frequent and aggressive brain tumors in adults. Lowergrade non-GBM tumors include grade II astrocytomas (AII) and oligodendrogliomas (OII). The least favorable prognosis is associated with GBM, which has a 5year survival rate around 5% (Ostrom et al, 2016). While histologic classification has been a valuable tool in clinical practice, significant differences in survival among patients of the same subtype have been observed, indicating underlying clinically significant molecular heterogeneity that has not yet been detected in all its ramifications

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