Characterizing multi‐PIK3CA mutations across cancer types: Toward precision oncology

Abstract

Abstract Background PIK3CA mutations are implicated in various cancers, but the implications of multiple concurrent mutations and their orientations within the gene have not been fully explored. Methods In this study, we analyzed multi‐PIK3CA mutations across a diverse pan‐cancer cohort comprising 3564 tumors. Results Multi‐PIK3CA mutations were present in 10.3% of all PIK3CA‐mutant tumors, predominantly occurring in breast and gynecological cancers. Notably, mutations within the helical domain (E542:E545) exclusively occurred in the trans‐orientation, contrasting with mutations in the kinase ABD and C2 domains, which mainly appeared in the cis orientation. Conclusions The distinct pattern of mutation orientations in PIK3CA suggests variable oncogenic potential, with helical domain mutations in the trans‐orientation potentially being less oncogenic. These findings highlight the importance of mutation orientation in the PIK3CA gene as potential biomarkers for targeted therapy. This understanding is crucial for designing clinical trials that leverage PI3K inhibitors, aiming for more effective and precise cancer treatment.

Keywords

• cis
• multi‐PIK3CA mutations
• PI3K inhibitor
• precision oncology
• trans