Molecular Interplay Between PTEN, ARID1A, PD-L1, and MMR in Asian Ovarian Clear Cell Carcinoma: Implications for Immunotherapy Response and Patient Stratification

Abstract

Ovarian clear cell carcinoma (OCCC) represents a distinct histological subtype with a high prevalence in Asian populations and poor chemotherapy response. This study investigated molecular interactions between phosphatase and tensin homolog (PTEN), AT-rich interactive domain 1A (ARID1A), programmed death-ligand 1 (PD-L1), and mismatch repair (MMR) proteins in Asian patients with OCCC. Immunohistochemical analysis was performed on tissue microarrays from 69 OCCC cases. The expression of PTEN, ARID1A, PD-L1, and four MMR proteins was evaluated alongside clinical data. A high prevalence of PTEN loss (78.3%) and ARID1A deficiency (48.8%), with PD-L1 expression in 26.1% and MMR deficiency in 10.1% of cases, was observed. All PD-L1-positive tumors demonstrated concurrent PTEN loss (p = 0.007). MMR deficiency was significantly associated with ARID1A loss (p = 0.049). PTEN loss correlated with worse progression-free survival (PFS) in early-stage disease (p = 0.039). PTEN and ARID1A alterations represent early pathogenic events in Asian OCCC, with PTEN loss significantly impacting PFS in early-stage disease. The correlation between PTEN loss and PD-L1 expression, alongside ARID1A-MMR deficiency association, provides insights into OCCC's immunological landscape and therapeutic vulnerabilities.

Keywords: ARID1A; PD-L1; PTEN; mismatch repair; ovarian clear cell carcinoma.

Figure 1

Representative images depicting immunohistochemical expression patterns of PTEN observed within ovarian clear cell carcinoma tissue specimens are presented: (A) strong cytoplasmic expression in >80% of tumor cells; (B) negative expression.

Figure 2

Representative images depicting immunohistochemical expression patterns of ARID1A observed within ovarian clear cell carcinoma tissue specimens are presented: (A) positive nuclear expression in >80% of tumor cells; (B) negative expression.

Figure 3

The images illustrate PD-L1 immunohistochemical staining patterns in ovarian clear cell carcinoma specimens: (A) tumor tissue demonstrating positive PD-L1 expression with a combined positive score (CPS) of 75%; (B) specimen exhibiting complete absence of PD-L1 expression.

Figure 4

Illustrative microphotographs showing the immunohistochemical staining patterns of mismatch repair (MMR) proteins in ovarian clear cell carcinoma tissue samples: (A) specimen displaying positive MLH1 protein expression; (B) tissue section demonstrating absence of MSH2 protein expression.

Figure 5

Kaplan–Meier analysis illustrates progression-free survival outcomes across all stages of ovarian clear cell carcinoma. (A) Stratified survival curves comparing patients with PTEN protein retention (red line) versus PTEN loss (blue line); log-rank test p = 0.056. (B) Stratified survival curves comparing patients with ARID1A protein retention (red line) versus ARID1A loss (blue line); log-rank test p = 0.090.

Figure 6

Kaplan–Meier curves illustrating progression-free survival in early-stage ovarian clear cell carcinoma patients. (A) Stratification by PTEN status: retained (red line) versus loss (blue line); log-rank test p = 0.039. (B) Stratification by ARID1A status: retained (red line) versus loss (blue line); log-rank test p = 0.405.