Clinical Research Directory

Epigenomic and Transcriptomic Analysis in BRCA Mutated Carriers With and Without Serous Tubal Intraepithelial Carcinoma

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy and is typically diagnosed at an advanced stage, limiting opportunities for early detection and intervention. Women carrying germline pathogenic variants in BRCA1 or BRCA2 have a substantially increased lifetime risk of developing HGSOC compared with the general population. Risk-reducing salpingo-oophorectomy (RRSO), currently the most effective preventive strategy for these women, has enabled the identification of isolated serous tubal intraepithelial carcinomas (STICs), which are now recognized as key precursor lesions in the serous carcinogenic pathway. Emerging evidence indicates that transcriptomic and epigenetic alterations associated with BRCA-related carcinogenesis may be present even in histologically normal tissues, suggesting that molecular changes precede the development of invasive disease. Characterizing these early alterations may improve understanding of ovarian cancer initiation and support the identification of biomarkers for risk assessment and early detection. Previous work demonstrated the feasibility and cost-effectiveness of a radiogenomic, ultrasound-based model capable of predicting germline BRCA1/2 status from imaging features of morphologically normal ovaries. However, the biological basis underlying these imaging signatures remains unclear. Defining the molecular differences between BRCA carriers and non-carriers may provide a mechanistic rationale for these radiogenomic findings and support future validation of imaging-based prediction models. This exploratory translational study will investigate transcriptomic and DNA methylation profiles in ovarian tissue samples from BRCA1/2 mutation carriers and BRCA wild-type controls. Three groups will be included: BRCA carriers undergoing RRSO without evidence of STIC lesions, BRCA carriers undergoing RRSO with unilateral STIC lesions and paired ovarian samples available, and presumed BRCA wild-type women undergoing adnexal surgery for benign gynecologic indications. The first objective is to identify baseline transcriptomic and epigenomic signatures that distinguish healthy ovaries from BRCA carriers and BRCA wild-type controls, thereby defining molecular features associated with hereditary predisposition. The second objective is to characterize molecular alterations associated with STIC lesions through comparison of STIC-containing ovarian samples with paired contralateral non-STIC ovarian tissue from the same BRCA carrier, allowing identification of lesion-associated changes while minimizing inter-individual variability. The third objective is to compare STIC-containing ovarian samples with healthy ovarian tissue from BRCA carrier controls to identify pathways involved in the earliest stages of serous tumorigenesis and the transition from genetic susceptibility to precursor lesion development. A total of 30 women will be included: 10 BRCA carriers without STIC lesions, 10 BRCA carriers with unilateral STIC lesions, and 10 BRCA wild-type controls. Integrated transcriptomic and DNA methylation analyses will be performed on available ovarian tissue samples. The resulting data are expected to improve understanding of the molecular landscape associated with BRCA-related ovarian cancer predisposition and early carcinogenesis, provide biological support for radiogenomic prediction models, and identify candidate biomarkers for future prevention and early-detection strategies.

Development and Validation of an Ovarian Cancer Risk Prediction Model for Family Members of Ovarian Cancer Probands

Ovarian cancer is the gynecological malignancy with the highest fatality rate, seriously threatening the life and health of women. One of the main reasons for its high fatality rate is that approximately 70% of patients are diagnosed at an advanced stage. Fortunately, about 1/5 of ovarian cancers are associated with genetic factors, providing us with an opportunity to screen high-risk populations and thereby prevent and diagnose the disease at an early stage and reduce the disease burden. Currently, research related to hereditary ovarian cancer in China is still very scarce, and clinical practice relies on data from foreign studies. However, hereditary tumors have distinct regional and ethnic characteristics, making it urgent to conduct clinical research based on the Chinese population to guide clinical practice in China. Current research suggests that approximately 50% - 60% of hereditary ovarian cancers are closely related to the BRCA1/2 genes. Therefore, accurately assessing the risk of ovarian cancer in BRCA1/2 germline mutation carriers is of great significance for the prevention and treatment of hereditary ovarian cancer.