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Published on: July 25, 2020
Expression of xeroderma pigmentosum A protein predicts improved outcome in metastatic ovarian carcinoma
Ellen V Stevens1, Mark Raffeld, Virginia Espina
1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Background:
The nucleotide excision repair (NER) proteins repair DNA adducts due to xenobiotics and cancer chemotherapy. The authors hypothesized that expression of the NER protein xeroderma pigmentosum A (XPA) would be reduced in a clinically significant fashion in metastatic ovarian carcinoma.
Methods:
Malignant effusion specimens were studied so that there was a uniform metastatic ovarian carcinoma population for study. XPA protein expression was analyzed by immunocytochemistry in 142 effusion specimens (109 peritoneal specimens, 33 pleural specimens) from 125 patients. Specimens were obtained at diagnosis (n = 76), and at disease recurrence (n = 66). Patients in the latter group received platinum-based chemotherapy.
Results:
XPA was expressed in cancer cells in 136 of the 142 (96%) effusion specimens. Strongest expression occurred in leukocytes and reactive mesothelial cells. XPA expression did not correlate with treatment status, effusion site, International Federation of Gynecology and Obstetrics stage, histologic grade, or the extent of residual disease. More effusion tumor cells from patients with a complete response to chemotherapy expressed XPA compared with those with a partial or no response (P = 0.03, chi(2) test). Patients with recurrent disease with XPA expressed in > 25% of tumor cells had better progression-free survival (PFS) by univariate analysis (median = 0 vs. 11 months, P < 0.001; 95% confidence interval [CI], 1-5, 8-14) and overall survival (OS; median = 24 vs. 34 months, P = 0.04; 95% CI, 17-31, 24-44). XPA was the only predictor of PFS outcome by multivariate analysis (P = 0.03).
Conclusions:
The results of the current study showed that XPA was widely expressed in metastatic ovarian carcinoma effusion specimens and in the cells of the effusion microenvironment. Paradoxically, XPA expression was associated with better response to chemotherapy and predicted better PFS and OS.
Insights
Xeroderma pigmentosum A (XPA) protein, involved in DNA repair, is widely expressed in metastatic ovarian cancer. Higher XPA expression paradoxically correlates with better chemotherapy response and improved patient survival outcomes.
Area of Science:
- Oncology
- Molecular Biology
- DNA Repair Mechanisms
Background:
- Nucleotide excision repair (NER) proteins are crucial for repairing DNA damage from xenobiotics and chemotherapy.
- The study investigated the expression of xeroderma pigmentosum A (XPA), an NER protein, in metastatic ovarian carcinoma.
- A hypothesis posited reduced XPA expression in clinically significant metastatic ovarian carcinoma.
Purpose of the Study:
- To analyze the expression levels of the xeroderma pigmentosum A (XPA) protein in metastatic ovarian carcinoma.
- To determine the correlation between XPA expression and clinical parameters, treatment response, and patient survival.
- To evaluate XPA as a potential prognostic biomarker in ovarian cancer.
Main Methods:
- Analysis of XPA protein expression using immunocytochemistry in 142 malignant effusion specimens from 125 ovarian carcinoma patients.
- Specimens were collected at diagnosis and disease recurrence, with a subset of patients having received platinum-based chemotherapy.
- Correlation of XPA expression with clinical factors including treatment status, effusion site, tumor stage, grade, and residual disease extent.
Main Results:
- XPA was detected in 96% of effusion specimens, with highest expression in leukocytes and mesothelial cells.
- XPA expression in tumor cells was associated with a complete response to chemotherapy.
- Increased XPA expression (>25% of tumor cells) predicted significantly better progression-free survival (PFS) and overall survival (OS) in recurrent disease.
- XPA emerged as the sole independent predictor of PFS via multivariate analysis.
Conclusions:
- Xeroderma pigmentosum A (XPA) is broadly expressed in metastatic ovarian carcinoma effusions and the tumor microenvironment.
- Contrary to initial hypotheses, XPA expression is paradoxically linked to improved chemotherapy response.
- XPA expression serves as a significant predictor of better progression-free and overall survival in ovarian cancer patients.
