Plasma Protein Biomarkers Associated with Higher Ovarian Cancer Risk in BRCA1/2 Carriers

Abstract

Ovarian cancer (OC) is the most lethal gynecologic malignancy and in-time diagnosis is limited because of the absence of effective biomarkers. Germline <i>BRCA1/2</i> genetic alterations are risk factors for hereditary OC; risk-reducing salpingo-oophorectomy (RRSO) is pursued for disease prevention. However, not all healthy carriers develop the disease. Therefore, identifying predictive markers in the <i>BRCA1/2</i> carrier population could help improve the identification of candidates for preventive RRSO. In this study, plasma samples from 20 OC patients (10 patients with <i>BRCA1/2</i> wild type (_wt) and 10 with the <i>BRCA1/2</i> variant (_var)) and 20 normal subjects (10 subjects with <i>BRCA1/2</i>_wt and 10 with <i>BRCA1/2</i>_var) were analyzed for potential biomarkers of hereditary OC. We applied a bottom-up proteomics approach, using nano-flow LC-MS to analyze depleted plasma proteome quantitatively, and potential plasma protein markers specific to the <i>BRCA1/2</i> variant were identified from a comparative statistical analysis of the four groups. We obtained 1505 protein candidates from the 40 subjects, and SPARC and THBS1 were verified by enzyme-linked immunosorbent assay. Plasma SPARC and THBS1 concentrations in healthy <i>BRCA1/2</i> carriers were found to be lower than in OC patients with <i>BRCA1/2</i>_var. If plasma SPARC concentrations increase over 337.35 ng/mL or plasma THBS1 concentrations increase over 65.28 μg/mL in a healthy <i>BRCA1/2</i> carrier, oophorectomy may be suggested.