Mutations: Are They a Relevant Target in Adult Diffuse Gliomas?

Gliomas are the most common and lethal malignant primary brain tumors in adults, associated with the highest number of years of potential life lost. The latest WHO classification for central nervous system tumors highlighted the need for new biomarkers of diagnosis, prognosis, and response to therapy. The PI3K/Akt signaling pathway is clearly implicated in tumorigenesis, being one of the most frequently altered pathways in cancer. Activating mutations are oncogenic and can influence both prognosis and treatment response in various tumor types. In gliomas, however, studies have reported inconsistent mutational frequencies, ranging from 0% to 30%. Furthermore, the impact of these alterations on glioma diagnosis, prognosis, and therapy response remains unclear. Current evidence suggests that mutations may represent early and constitutive events in glioma development, associated with worse glioblastoma prognoses, earlier recurrences, and widespread disease. Among these, the hotspot mutation H1047R has been particularly associated with a more aggressive phenotype while also modulating the neuronal microenvironment. In this review, we examine the clinical relevance of mutations across different cancers, with a particular focus on their emerging role in glioma. Moreover, we also discuss the therapeutic potential and challenges of targeting mutations in the context of glioma.