PIK3CA Mutations in Diffuse Gliomas: An Update on Molecular Stratification, Prognosis, Recurrence, and Aggressiveness

Abstract

Introduction: PIK3CA is one of the most mutated oncogenes in solid tumors. In breast cancer (ER-positive, HER2-negative), these events represent a predictive biomarker of response to alpelisib. In glioblastomas (GBM), PIK3CA mutations were described as early constitutive events. Here, we investigated PIK3CA mutational profile across glioma molecular subgroups and its relevance during glioma recurrence. Furthermore, PIK3CA mutations’ effect in PI3K pathway, prognosis, and response to therapy was also explored. Material and Methods: Exons 10 and 21 of PIK3CA mutations were evaluated in 394 gliomas and 19 glioma recurrences from Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) and compared with The Cancer Genome Atlas (TCGA) data. TIMER2.0 and NetMHCpan4.1 were used to assess the immune-microenvironment contribution. Results: PIK3CA mutations were identified among all glioma subgroups, although with no impact on their stratification or prognosis. In both cohorts (IPOLFG and TCGA), PIK3CA mutation frequencies in IDH-mutant and IDH-wild-type GBM were similar (IPOLFG: 9% and 3%; TCGA: 8% and 2%). These mutations were not mutually exclusive with PTEN deletion and EGFR amplification. Despite their reduced frequency, we discovered PIK3CA mutations were maintained during glioma recurrence regardless of administered therapies. The immune microenvironment might not contribute to this phenotype as PIK3CA mutations did not influence immune cell infiltration. Conclusions: Despite the absence of a predominant effect in glioma stratification, PIK3CA mutations were maintained during glioma recurrence, possibly contributing to glioma cell survival, representing promising therapeutic targets in recurrent glioma. Nevertheless, understanding the potential synergistic effects between PIK3CA mutations, PTEN deletion, and EGFR amplification is pivotal to targeted therapies’ efficiency.

Genetic profiling of rat gliomas and cardiac schwannomas from life-time radiofrequency radiation exposure study using a targeted next-generation sequencing gene panel

“…Similarly in cardiac schwannomas, 12/26 (46%) Pik3ca NS variants were described in COSMIC without relevance to central nervous system tumors. Interestingly, we detected a c.3040C>T nonsense mutation in 3/14 gliomas which is not in the COSMIC database but was reported as a human nonsense mutation [ 32 ]. These results suggest that Pik3ca mutations might be associated with rat glioma and schwannoma tumor progression but the relationship to tumor type seem to differ between human and rat.…”

Integrated network pharmacology and experimental verification to reveal the role of Shezhi Huangling Decoction against glioma by inactivating PI3K/Akt-HIF1A axis

“…PIK3CA is one of the homologous isoforms of Class IA PI3K that encode catalytic subunits p110α. Meanwhile, Brito et al point out that PIK3CA mutations occur frequently and maintain cell survival in glioma recurrence [ 45 ]. ERBB2 belongs to the transmembrane protein receptor of the tyrosine kinase I subfamily and is highly expressed in various types of GBM [ 46 , 47 ].…”

An expanded role for surgery in grade 3 1p/19q co-deleted oligodendroglioma

“… 27 PI3K mutations have also been identified in low-grade gliomas, but their prognostic value remains unknown in this pathology. 28 , 29 …”