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

Official title

Epigenomic and Transcriptomic Analysis in BRCA Mutated Carriers With and Without Serous Tubal Intraepithelial Carcinoma (STIC): a Preliminary Study for the Refinement of Biomarker Discovery

Overview

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.

Interventions

• Diagnostic test Peripheral blood sampling performed for germline DNA extraction and assessment of BRCA1/2 mutation status.
  Peripheral blood sampling for germline DNA extraction and BRCA1/2 testing will be performed exclusively in participants enrolled in Group B (presumed BRCA wild-type controls) to confirm the absence of germline BRCA1/2 pathogenic variants.

Primary outcome measures

• Transcriptomic and Epigenomic Signatures Associated with BRCA Status and STIC Lesions [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

Group A.1:

• Age ≥ 18 years
• Signed informed consent
• Documented germline BRCA1/2 pathogenic variant
• Ovarian tissue with no histopathological abnormalities
• Availability of archived FFPE tissue from both ovaries
• Availability of fimbrial tissue, when present in the archived material

Group A.2:

• Age ≥ 18 years
• Signed informed consent
• Documented germline BRCA1/2 pathogenic variant
• Ovarian tissue with no histopathological abnormalities
• Histologically confirmed unilateral STIC lesion
• Availability of archived FFPE tissue from both ovaries
• Availability of fimbrial tissue (including fimbria with and without STIC), when present in the archived material

Group B:

• Age ≥ 18 years
• Signed informed consent
• Documented germline BRCA1/2 wild-type
• Ovarian tissue with no histopathological abnormalities
• Availability of archived FFPE tissue from at least one ovary
• Availability of fimbrial tissue, when present in the archived material

Exclusion criteria

• Age < 18 years
• Previous or concurrent diagnosis of invasive ovarian, tubal, or peritoneal carcinoma
• History of neoadjuvant chemotherapy or pelvic radiotherapy prior to tissue collection
• Presence of bilateral STIC lesions
• Ovarian or tubal tissue with histopathological abnormalities other than those specified in the inclusion criteria
• Inadequate quantity or poor quality of archived FFPE tissue for molecular analyses
• Lack of documented germline BRCA1/2 status

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Other

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07736300 · 27298

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗