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

SIMPLE SUMMARY: Most hereditary ovarian cancer is associated with BRCA1/2 variants, and risk-reducing salpingo-oophorectomy during the follow-up monitoring of ovarian cancer development in heathy women with the BRCA1/2 variant reduces ovarian cancer incidence. The aim of this study was to identify plasma protein biomarkers that can indicate an increased risk of developing ovarian cancer using a proteomic approach based on a population of genetic variants. Two identified biomarkers among differentially expressed proteins, SPARC and THBS1, had lower plasma concentrations in healthy BRCA1/2 variant carriers than in ovarian cancer patients with the BRCA1/2 variant; concentration of two proteins increased at the onset of ovarian cancer. These protein markers from non-invasive liquid biopsy sampling could be used to help women with the BRCA1/2 variant determine whether to undergo an oophorectomy that could potentially affect the quality of life. ABSTRACT: Ovarian cancer (OC) is the most lethal gynecologic malignancy and in-time diagnosis is limited because of the absence of effective biomarkers. Germline BRCA1/2 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 BRCA1/2 carrier population could help improve the identification of candidates for preventive RRSO. In this study, plasma samples from 20 OC patients (10 patients with BRCA1/2 wild type ((wt)) and 10 with the BRCA1/2 variant ((var))) and 20 normal subjects (10 subjects with BRCA1/2(wt) and 10 with BRCA1/2(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 BRCA1/2 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 BRCA1/2 carriers were found to be lower than in OC patients with BRCA1/2(var). If plasma SPARC concentrations increase over 337.35 ng/mL or plasma THBS1 concentrations increase over 65.28 μg/mL in a healthy BRCA1/2 carrier, oophorectomy may be suggested.