Molecular Interplay Between PTEN, ARID1A, PD-L1, and MMR in Asian Ovarian Clear Cell Carcinoma: Implications for Immunotherapy Response and Patient Stratification
Abstract
1. Introduction
2. Results
2.1. Clinicopathological Characteristics of Included Patients
2.2. Expression Patterns According to Disease Stage and Molecular Interrelationships Between Biomarkers
2.3. Co-Expression Analysis of ARID1A and PTEN According to Disease Stage
2.4. Treatment Response and Survival Analysis
3. Discussion
3.1. Distinct Molecular Characteristics of ARID1A and PTEN Expression Patterns in Asian OCCC Cohort: Early Alterations and Stage-Specific Dynamics
3.2. PTEN Loss as an Early Prognostic Indicator in OCCC: Implications for Stage-Specific Therapeutic Strategies
3.3. MMR Deficiency and PI3K–AKT–mTOR Pathway: Molecular Interplay in Immune Evasion
3.4. ARID1A-MMR Relationship: Implications for DNA Repair and Immunotherapy Response
3.5. PTEN-PD-L1 Axis: Targeting Immune Checkpoint Pathways in OCCC
3.6. Limitations
4. Materials and Methods
4.1. Patients and Settings
4.2. Assembling of Tissue Array
4.3. Immunohistochemistry Study of Targeted Biomarkers
4.4. Definition for ARID1A and PTEN Expressions
4.5. Definition of Positive PD-L1 and Deficient Expression of MMR Proteins
4.6. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
OCCC | Ovarian clear cell carcinoma |
PTEN | Phosphatase and tensin homolog |
ARID1A | AT-rich interactive domain 1A |
PD-L1 | Programmed cell death-ligand 1 |
MMR | Mismatch repair |
IHC | Immunohistochemistry |
dMMR | Deficient mismatch repair |
pMMR | Proficient mismatch repair |
CPS | Combined positive score |
PFS | Progression-free survival |
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Characteristic | Value |
---|---|
Age, mean (SD) | 50.6 (9.2) |
Follow-up, months, median (range) | 50 (5–132) |
FIGO stage, n (%) | |
I | 36 (52.2) |
II | 8 (11.6) |
III | 18 (26.1) |
IV | 6 (8.7) |
Unknown | 1 (1.4) |
Concurrent endometriosis | |
Yes | 15 (21.7) |
No | 54 (78.3) |
ARID1A expression, n (%) | |
Intact | 41 (51.2) |
Altered | 39 (48.8) |
PTEN expression, n (%) | |
Strong | 15 (21.7) |
Weak or loss | 54 (78.3) |
MMR status, n (%) | |
Proficient | 62 (89.9) |
Deficient | 7 (10.1) |
PD-L1 expression, n (%) | |
Positive | 18 (26.1.) |
Negative | 51 (73.9) |
Total Number n = 69, 100% | pMMR n = 62, 89.9% | dMMR- n = 7, 10.1% | p-Value | PD-L1 (+) n = 18, 26.1% | PD-L1 (-) n = 51, 73.9% | p-Value |
---|---|---|---|---|---|---|
Variables | n (%) | n (%) | ||||
Age Mean (SD) | 50.6 (8.89) | 51.0 (12.3) | 0.903 | 50.2 (7.67) | 50.8 (9.73) | 0.835 |
FIGO Stage * I/II III/IV | 38 (63.3) 22 (36.7) | 5 (71.4) 2 (28.6) | 1.000 | 11(61.1) 7 (38.9) | 32 (65.3) 17 (34.7) | 0.751 |
Platinum sensitivity ** Sensitive Resistant | 42 (75.0) 14 (25.0) | 4 (66.7) 2 (33.3) | 0.643 | 14 (77.8) 4 (22.2) | 32 (72.7) 12 (27.3) | 0.760 |
ARID1A expression Retained Loss | 35 (56.5) 27 (43.5) | 1 (14.3) 6 (85.7) | 0.049 | 8 (44.4) 10(55.6) | 28 (54.9) 23 (45.1) | 0.445 |
PTEN expression Retained Loss | 15 (24.2) 47 (75.8) | 0 (0) 7 (100) | 0.333 | 0 (0) 18 (100) | 15 (29.4) 36 (70.6) | 0.007 |
PD-L1 expression Positive Negative | 17 (27.4) 45 (72.6) | 1 (14.3) 6 (85.7) | 0.667 | NA | NA | NA |
MMR status Proficient Deficient | NA | NA | NA | 17 (94.4) 1 (5.6) | 45 (88.2) 6 (11.8) | 0.667 |
Stage | A+/P+ | A+/P- | A-/P+ | A-/P- | p-Value |
---|---|---|---|---|---|
Early (n = 44) | 3 (6.8) | 16 (36.4) | 5 (11.4) | 20 (45.4) | 1.000 |
Advanced (n = 24) | 6 (25.0) | 10 (41.7) | 0 (0.0) | 8 (33.3) | 0.066 |
Total * (n = 69) | 10 (14.5) | 26 (37.7) | 5 (7.2) | 28 (40.36) | 0.204 |
Antibody | Clone | Dilution | Manufacturer |
---|---|---|---|
ARID1A | - | 1:2000 | Sigma (HPA005456) |
PTEN | - | 1:200 | Cell Signaling (#9559) |
MLH1 | GM011 | 1:50 | Genemed |
MSH2 | G219-1129 | 1:100 | ZETA |
MSH6 | GM024 | 1:100 | Genemed |
PMS2 | A16-4 | 1:100 | BD Biosciences |
PD-L1 | 22C3 | 1:50 | Agilent (GE00621-2) |
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Wu, C.-H.; Lin, H.; Ou, Y.-C.; Fu, H.-C.; Yang, M.-Y.; Huang, C.-C. Molecular Interplay Between PTEN, ARID1A, PD-L1, and MMR in Asian Ovarian Clear Cell Carcinoma: Implications for Immunotherapy Response and Patient Stratification. Int. J. Mol. Sci. 2025, 26, 4915. https://doi.org/10.3390/ijms26104915
Wu C-H, Lin H, Ou Y-C, Fu H-C, Yang M-Y, Huang C-C. Molecular Interplay Between PTEN, ARID1A, PD-L1, and MMR in Asian Ovarian Clear Cell Carcinoma: Implications for Immunotherapy Response and Patient Stratification. International Journal of Molecular Sciences. 2025; 26(10):4915. https://doi.org/10.3390/ijms26104915
Chicago/Turabian StyleWu, Chen-Hsuan, Hao Lin, Yu-Che Ou, Hung-Chun Fu, Ming-Yu Yang, and Chao-Cheng Huang. 2025. "Molecular Interplay Between PTEN, ARID1A, PD-L1, and MMR in Asian Ovarian Clear Cell Carcinoma: Implications for Immunotherapy Response and Patient Stratification" International Journal of Molecular Sciences 26, no. 10: 4915. https://doi.org/10.3390/ijms26104915
APA StyleWu, C.-H., Lin, H., Ou, Y.-C., Fu, H.-C., Yang, M.-Y., & Huang, C.-C. (2025). Molecular Interplay Between PTEN, ARID1A, PD-L1, and MMR in Asian Ovarian Clear Cell Carcinoma: Implications for Immunotherapy Response and Patient Stratification. International Journal of Molecular Sciences, 26(10), 4915. https://doi.org/10.3390/ijms26104915