PIK3CA mutations and PI3K isoform expression define prognostic signatures in ovarian clear cell carcinoma

PURPOSE: Ovarian clear cell carcinoma (OCCC) is frequently characterized by dysregulation of the PI3K/AKT/mTOR (PAM) pathway; however, the expression patterns and clinical significance of class I PI3K catalytic isoforms remain incompletely understood. This study aimed to comprehensively evaluate PI3K catalytic subunit expression, co-expression patterns, and their prognostic relevance in OCCC. METHODS: A retrospective cohort of 100 patients with OCCC was analyzed. Immunohistochemistry was performed to assess the expression of p110α, p110β, p110δ, p110γ, and pAKT. PIK3CA exon 9 and exon 20 mutations were evaluated in available formalin-fixed paraffin-embedded tissues. Associations between PI3K isoforms, pAKT activation, clinicopathological characteristics, and survival outcomes were investigated. RESULTS: The expression positivity rates of the four class I PI3K catalytic subunits in OCCC were 86% for p110γ, 77% for p110α, 58% for p110δ, and 56% for p110β. p110α and p110β were positively associated with pAKT activation, whereas p110δ and p110γ showed no significant association. p110δ expression was significantly correlated with PI3KCA exon9 mutation. Frequent co-expression of multiple PI3K catalytic subunits was observed, with simultaneous expression of all four isoforms representing the predominant pattern and significantly correlating with pAKT positivity. In advanced-stage disease, p110β expression was significantly associated with poorer progression-free survival (PFS), while pAKT positivity correlated with worse overall survival (OS) and PFS. CONCLUSIONS: OCCC displays substantial heterogeneity in PI3K catalytic isoform expression and co-expression. p110α and p110β were associated with pAKT activation. In advanced-stage OCCC, high p110β expression was associated with poorer PFS, whereas pAKT activation was associated with both poorer PFS and OS, supporting further investigation of PI3K-targeted therapeutic strategies.