MicroRNA expression signatures for the prediction of BRCA1/2 mutation-associated hereditary breast cancer in paraffin-embedded formalin-fixed breast tumors

作者：Tanic Miljana; Yanowski Kira; Gomez Lopez Gonzalo; Socorro Rodriguez Pinilla Maria; Marquez Rodas Ivan; Osorio Ana; Pisano David G; Martinez Delgado Beatriz; Benitez Javier^*

来源：International Journal of Cancer, 2015, 136(3): 593-602.

DOI：10.1002/ijc.29021

• hereditary breast cancer
• miRNA
• BRCA1
• BRCA2
• diagnostic biomarker

Screening for germline mutations in breast cancer-associated genes BRCA1 and BRCA2 is indicated for patients with breast cancer from high-risk breast cancer families and influences both treatment options and clinical management. However, only 25% of selected patients test positive for BRCA1/2 mutation, indicating that additional diagnostic biomarkers are necessary. We analyzed 124 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients with hereditary (104) and sporadic (20) invasive breast cancer, divided into two series (A and B). Microarray expression profiling of 829 human miRNAs was performed on 76 samples (Series A), and bioinformatics tool Prophet was used to develop and test a microarray classifier. Samples were stratified into a training set (n=38) for microarray classifier generation and a test set (n=38) for signature validation. A 35-miRNA microarray classifier was generated for the prediction of BRCA1/2 mutation status with a reported 95% (95% CI=0.88-1.0) and 92% (95% CI: 0.84-1.0) accuracy in the training and the test set, respectively. Differential expression of 12 miRNAs between BRCA1/2 mutation carriers versus noncarriers was validated by qPCR in an independent tumor series B (n=48). Logistic regression model based on the expression of six miRNAs (miR-142-3p, miR-505*, miR-1248, miR-181a-2*, miR-25* and miR-340*) discriminated between tumors from BRCA1/2 mutation carriers and noncarriers with 92% (95% CI: 0.84-0.99) accuracy. In conclusion, we identified miRNA expression signatures predictive of BRCA1/2 mutation status in routinely available FFPE breast tumor samples, which may be useful to complement current patient selection criteria for gene testing by identifying individuals with high likelihood of being BRCA1/2 mutation carriers.
What's New? Screening for germline mutations in BRCA1 and BRCA2 genes is indicated for breast cancer patients from high-risk breast cancer families to inform both treatment options and clinical management. However, currently only 25% of selected patients test positive for BRCA1/2 mutation, calling for additional diagnostic biomarkers. Here, BRCA1 and BRCA2 breast tumors presented highly homogeneous miRNA expression profiles and could be differentiated from familial non-BRCA1/2 (BRCAX) and sporadic breast tumors based on unique miRNA expression signatures with 92% accuracy, in routinely available FFPE breast tumors samples. These signatures may be useful for complementing current patient selection criteria for BRCA1/2 gene testing.

• 出版日期2015-2-15