Identification of BRCA1/2 mutation female carriers using circulating microRNA profiles

Kevin Elias, Urszula Smyczynska, Konrad Stawiski, Zuzanna Nowicka, James Webber, Jakub Kaplan, Charles Landen, Jan Lubinski, Asima Mukhopadhyay, Dona Chakraborty, Denise C. Connolly, Heather Symecko, Susan M. Domchek, Judy E. Garber, Panagiotis Konstantinopoulos, Wojciech Fendler () and Dipanjan Chowdhury ()
Additional contact information
Kevin Elias: Brigham and Women’s Hospital
Urszula Smyczynska: Medical University of Lodz
Konrad Stawiski: Medical University of Lodz
Zuzanna Nowicka: Medical University of Lodz
James Webber: Brigham and Women’s Hospital
Jakub Kaplan: Dana-Farber Cancer Institute
Charles Landen: University of Virginia
Jan Lubinski: International Hereditary Cancer Center of the Pomeranian Medical University
Asima Mukhopadhyay: Kolkata Gynecology Oncology Trials and Translational Research Group
Dona Chakraborty: Kolkata Gynecology Oncology Trials and Translational Research Group
Denise C. Connolly: Fox Chase Cancer Center
Heather Symecko: University of Pennsylvania
Susan M. Domchek: University of Pennsylvania
Judy E. Garber: Dana-Farber Cancer Institute
Panagiotis Konstantinopoulos: Dana-Farber Cancer Institute
Wojciech Fendler: Medical University of Lodz
Dipanjan Chowdhury: Dana-Farber Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38925-4

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