Molecular profiling of gliomas: potential therapeutic implications

Abstract

Gliomas are the most common primary malignant brain tumor. Over the last decade, significant advances have been made in the molecular characterization of this tumor group, identifying predictive biomarkers or molecular actionable targets, and paving the way to molecular-based targeted therapies. This personalized therapeutic approach is effective and illustrated in the present review. Among many molecular abnormalities, BRAF mutation and mTOR activation in pilocytic astrocytomas and subependymal giant cell astrocytomas are actionable targets sensitive to vemurafenib and everolimus, respectively. Chromosome arms 1p/19q co-deletion and IDH mutational status are pivotal in driving delivery of early procarbazine, lomustine and vincristine chemotherapy in anaplastic oligodendroglial tumors. Although consensus to assess MGMT promoter methylation is not reached yet, it may be useful in predicting resistance to temozolomide in elderly patients.

Keywords:

• genomics
• glioblastoma
• kinase inhibitors
• molecular profiling
• targeted therapies

Financial & competing interests disclosure

S Kesari has received funding from the NIH and NCI, Voices against Brain Cancer, the Tuttleman Family Foundation, and the Christopher and Bronwen Gleeson Family Trust. A Idbaih has received research funding from Intsel Chimos and Beta Innov. A Idbaih has also received travel and meeting funding from Hoffman-La Roche and lecture funding from Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Neuro-oncology enters the era of integrated personalized medicine including not only clinical, radiological and pathological, but also molecular characteristics of patients and their tumors.

• BRAF mutational status needs to be tested in WHO grade I glioma patients searching for druggable BRAF mutation.

• Assessment of chromosome arm 1p/19q and IDH mutational statuses is now mandatory for an optimal medical management of WHO grade III glioma patients.

• MGMT methylation status has a predictive and prognostic value in WHO grade IV glioblastoma patients.

• The best way to assess MGMT methylation status is debated, preventing its implementation in clinical routine.

• ATRX mutation is associated with astrocytic phenotype in WHO grade II and III gliomas.

• TERT mutation is associated with glioblastoma and 1p/19q co-deleted oligodendroglial tumor, regardless of WHO grade of malignancy.

• Intertumor and intratumor heterogeneity of gliomas is also observed at the molecular level.

Notes