Clinical and immunological correlates of long term survival in glioblastoma

Glioblastoma (GBM) is the most common and most aggressive type of primary brain tumour in adults. It represents 54% of all gliomas and 16% of all brain tumours (Ostrom et al. 2016). Despite surgery and treatment with radiotherapy plus an oral alkylating agent, temozolomide (TMZ), tumours invariably recur, and the patient survival is an average of ~14-16 months. In this review we summarise the current understanding of multiple factors that may affect survival of patients with GBMs. In particular, we discuss recent advancements in surgery and detection of genomic-based markers with prognostic values, such as IDH1/2 mutations, MGMT gene promoter methylation, and TERT gene promoter alterations. We address the issue of tumour heterogeneity and evolution that may result in different parts of the same tumour exhibiting different GBM subtypes and in subtype switching, which may restrict the usefulness of the expression-based classification as a prognostic marker before relapse. The determinants of long-term survival in patients with IDH1/2wt GBM, beyond MGMT promoter methylation, remain to be identified, and even the absence of both IDH1/2 mutations and MGMT promoter methylation does not preclude long-term survival. These findings suggest that host-derived factors, such as immune system responsiveness may contribute to long-term survival in such patients. We report the results of high-throughput approaches, suggesting links between long-term survival and enhanced immune-related gene expression. The further search for new gene candidates, promoter methylation status, and specific features of host immunity should provide prognostic biomarkers for the evaluation of survival of IDH1 wild-type/non-G-CIMP GBMs.