Tomás Ana, Pojo Marta
Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Lisboa Francisco Gentil (IPOLFG) E.P.E., 1099-023 Lisbon, Portugal.
NOVA Medical School, NOVA University of Lisbon, 1169-056 Lisbon, Portugal.
Int J Mol Sci. 2025 May 30;26(11):5276. doi: 10.3390/ijms26115276.
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.
神经胶质瘤是成人中最常见且致命的原发性恶性脑肿瘤，与潜在生命损失年数最多相关。世界卫生组织（WHO）最新的中枢神经系统肿瘤分类强调了对诊断、预后和治疗反应新生物标志物的需求。PI3K/Akt信号通路显然与肿瘤发生有关，是癌症中最常发生改变的通路之一。激活突变具有致癌性，可影响多种肿瘤类型的预后和治疗反应。然而，在神经胶质瘤中，研究报告的突变频率不一致，范围从0%到30%。此外，这些改变对神经胶质瘤诊断、预后和治疗反应的影响仍不清楚。目前的证据表明，突变可能代表神经胶质瘤发展中的早期和组成性事件，与胶质母细胞瘤预后较差、复发较早和疾病广泛相关。其中，热点突变H1047R尤其与更具侵袭性的表型相关，同时还调节神经元微环境。在本综述中，我们研究了不同癌症中突变的临床相关性，特别关注它们在神经胶质瘤中新兴的作用。此外，我们还讨论了在神经胶质瘤背景下靶向突变的治疗潜力和挑战。
