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Elias, Kevin; Smyczynska, Urszula; Stawiski, Konrad; Nowicka, Zuzanna; Webber, James; Kaplan, Jakub; Landen, Charles; Lubinski, Jan; Mukhopadhyay, Asima; Chakraborty, Dona; Connolly, Denise C; Symecko, Heather; Domchek, Susan M; Garber, Judy E; Konstantinopoulos, Panagiotis; Fendler, Wojciech; Chowdhury, Dipanjan
Nature communications, 06/2023, Letnik: 14, Številka: 1Journal Article
Identifying germline BRCA1/2 mutation carriers is vital for reducing their risk of breast and ovarian cancer. To derive a serum miRNA-based diagnostic test we used samples from 653 healthy women from six international cohorts, including 350 (53.6%) with BRCA1/2 mutations and 303 (46.4%) BRCA1/2 wild-type. All individuals were cancer-free before and at least 12 months after sampling. RNA-sequencing followed by differential expression analysis identified 19 miRNAs significantly associated with BRCA mutations, 10 of which were ultimately used for classification: hsa-miR-20b-5p, hsa-miR-19b-3p, hsa-let-7b-5p, hsa-miR-320b, hsa-miR-139-3p, hsa-miR-30d-5p, hsa-miR-17-5p, hsa-miR-182-5p, hsa-miR-421, hsa-miR-375-3p. The final logistic regression model achieved area under the receiver operating characteristic curve 0.89 (95% CI: 0.87-0.93), 93.88% sensitivity and 80.72% specificity in an independent validation cohort. Mutated gene, menopausal status or having preemptive oophorectomy did not affect classification performance. Circulating microRNAs may be used to identify BRCA1/2 mutations in patients of high risk of cancer, offering an opportunity to reduce screening costs.
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