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Published on: October 14, 2015
BRCAness profile of sporadic ovarian cancer predicts disease recurrence
Weiya Z Wysham1, Paulette Mhawech-Fauceglia, Hong Li
1Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, United States of America.
Background:
The consequences of defective homologous recombination (HR) are not understood in sporadic ovarian cancer, nor have the potential role of HR proteins other than BRCA1 and BRCA2 been clearly defined. However, it is clear that defects in HR and other DNA repair pathways are important to the effectiveness of current therapies. We hypothesize that a subset of sporadic ovarian carcinomas may harbor anomalies in HR pathways, and that a BRCAness profile (defects in HR or other DNA repair pathways) could influence response rate and survival after treatment with platinum drugs. Clinical availability of a BRCAness profile in patients and/or tumors should improve treatment outcomes.
Objective:
To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival.
Materials And Methods:
Protein microarray analysis of ovarian cancer tissue was used to determine protein expression levels for defined DNA repair proteins. Correlation with clinical and pathologic parameters in 186 patients with advanced stage III-IV and grade 3 ovarian cancer was analyzed using Chi square, Kaplan-Meier method, Cox proportional hazard model, and cumulative incidence function.
Results:
High PARP, FANCD2 and BRCA1 expressions were significantly correlated with each other; however, elevated p53 expression was associated only with high PARP and FANCD2. Of all patients, 9% recurred within the first year. Among early recurring patients, 41% had high levels of PARP, FANCD2 and P53, compared to 19.5% of patients without early recurrence (p = 0.04). Women with high levels of PARP, FANCD2 and/or P53 had first year cumulative cancer incidence of 17% compared with 7% for the other groups (P = 0.03).
Conclusions:
Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression are at increased risk of early ovarian cancer recurrence and platinum resistance.
Insights
High levels of PARP, FANCD2, and P53 proteins indicate a higher risk of early ovarian cancer recurrence and platinum resistance. Understanding BRCAness profiles can improve treatment outcomes for ovarian cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Defects in homologous recombination (HR) and DNA repair pathways are crucial for sporadic ovarian cancer treatment efficacy.
- The role of HR proteins beyond BRCA1/BRCA2 in ovarian cancer is not fully understood.
- A BRCAness profile may predict response to platinum-based therapies in ovarian cancer.
Purpose of the Study:
- To define the BRCAness profile in sporadic ovarian carcinoma.
- To investigate the correlation between BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression and treatment response, recurrence, and survival.
- To assess the clinical utility of a BRCAness profile for improving ovarian cancer treatment outcomes.
Main Methods:
- Protein microarray analysis of 186 advanced-stage, high-grade ovarian cancer tissues.
- Assessment of DNA repair protein expression including BRCA1, PARP, and FANCD2.
- Statistical analysis using Chi square, Kaplan-Meier, Cox proportional hazard model, and cumulative incidence function to correlate protein expression with clinical parameters.
Main Results:
- Concomitant high expression of PARP, FANCD2, and BRCA1 was observed.
- Elevated P53 expression correlated with high PARP and FANCD2 levels.
- Patients with high PARP, FANCD2, and/or P53 expression showed a significantly higher incidence of early recurrence (17% vs 7%) and were at increased risk for first-year recurrence (41% vs 19.5%).
Conclusions:
- Concomitant high levels of PARP, FANCD2, and P53 protein expression are associated with increased risk of early ovarian cancer recurrence.
- These protein expression patterns may predict platinum resistance in ovarian cancer.
- Identifying a BRCAness profile could guide personalized treatment strategies and improve patient outcomes.
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