Identification of BRCA1/2 mutation carriers using circulating microRNA profiles

Identifying germline BRCA1 or 2 mutation carriers is vital for reducing their risk of breast and ovarian cancer; however, many carriers are not referred for genetic testing. While population-wide testing is not feasible, a cheap functional screen for phenotypic BRCAness could guide efforts for focused genetic counseling and improve cancer prevention and early detection. The aim of this study was to derive a serum-based miRNA panel to identify BRCA1 or 2 mutation carriers among healthy controls. We performed a diagnostic biomarker study based on serum samples collected between by six international cohorts. In all individuals, we isolated and quantified miRNAs expression using RNA-sequencing. The classification model achieved AUC ROC 0.89 and 85.61 percent accuracy, 93.88 sensitivity and 80.72 specificity in the validation group. Mutation of either BRCA1 or BRCA2, menopausal status or having preemptive oophorectomy before blood sample draw did not affect classification performance. Circulating microRNAs may be used to identify BRCA1 or BRCA2 mutations in patients of high genetic risk of ovarian and breast cancer, facilitating cheap first line screening for further genetics studies.