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Triple negative breast cancer (TNBC), a clinically aggressive breast cancer subtype, affects 15–35% of women from Latin America. Using an approach of direct integration of copy number and global miRNA profiling data, performed simultaneously in the same tumor specimens, we identified a panel of 17 miRNAs specifically associated with TNBC of ancestrally characterized patients from Latin America, Brazil. This panel was differentially expressed between the TNBC and non-TNBC subtypes studied (p ≤ 0.05, FDR ≤ 0.25), with their expression levels concordant with the patterns of copy number alterations (CNAs), present mostly frequent at 8q21.3-q24.3, 3q24-29, 6p25.3-p12.2, 1q21.1-q44, 5q11.1-q22.1, 11p13-p11.2, 13q12.11-q14.3, 17q24.2-q25.3 and Xp22.33-p11.21. The combined 17 miRNAs presented a high power (AUC = 0.953 (0.78–0.99);95% CI) in discriminating between the TNBC and non-TNBC subtypes of the patients studied. In addition, the expression of 14 and 15 of the 17miRNAs was significantly associated with tumor subtype when adjusted for tumor stage and grade, respectively. In conclusion, the panel of miRNAs identified demonstrated the impact of CNAs in miRNA expression levels and identified miRNA target genes potentially affected by both CNAs and miRNA deregulation. These targets, involved in critical signaling pathways and biological functions associated specifically with the TNBC transcriptome of Latina patients, can provide biological insights into the observed differences in the TNBC clinical outcome among racial/ethnic groups, taking into consideration their genetic ancestry.

// Bruna Sugita 1 , Mandeep Gill 2 , Akanskha Mahajan 2 , Anju Duttargi 2 , Saurabh Kirolikar 2 , Rodrigo Almeida 1 , Kenny Regis 2 , Olusayo L. Oluwasanmi 2 , Fabio Marchi 3 , Catalin Marian 4, 8 , Kepher Makambi 2, 5 , Bhaskar Kallakury 6 , Laura Sheahan 7 , Iglenir J.Cavalli 1 , Enilze M. Ribeiro 1 , Subha Madhavan 2, 7 , Simina Boca 2, 7 , Yuriy Gusev 2, 7 , Luciane R. Cavalli 2 1 Department of Genetics, Federal University of Parana, Curitiba, PR, Brazil 2 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 3 International Research Center-CIPE, A. C. Camargo Cancer Center, Sao Paulo, SP, Brazil 4 The Ohio State University Comprehensive Cancer Center, Division of Cancer Prevention and Control, College of Medicine, The Ohio State University, Columbus, Ohio 5 Departments of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University, Washington, DC USA 6 Department of Pathology, Georgetown University Medical Center, Washington, DC, USA 7 Innovation Center for Biomedical Informatics, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 8 The University of Medicine and Pharmacy Timisoara, Timisoara, Romania Correspondence to: Luciane R. Cavalli, email: lrc@georgetown.edu Keywords: microRNA, triple negative breast cancer, African American, non-Hispanic white, copy number Received: July 02, 2016 Accepted: October 25, 2016 Published: November 02, 2016 ABSTRACT Triple Negative Breast Cancer (TNBC), a clinically aggressive subtype of breast cancer, disproportionately affects African American (AA) women when compared to non-Hispanic Whites (NHW). MiRNAs(miRNAs) play a critical role in these tumors, through the regulation of cancer driver genes. In this study, our goal was to characterize and compare the patterns of miRNA expression in TNBC of AA ( n = 27) and NHW women ( n = 30). A total of 256 miRNAs were differentially expressed between these groups, and distinct from the ones observed in their respective non-TNBC subtypes. Fifty-five of these miRNAs were mapped in cytobands carrying copy number alterations (CNAs); 26 of them presented expression levels concordant with the observed CNAs. Receiving operating characteristic (ROC) analysis showed a good power (AUC ≥ 0.80; 95% CI) for over 65% of the individual miRNAs and a high combined power with superior sensitivity and specificity (AUC = 0.88 (0.78−0.99); 95% CI) of the 26 miRNA panel in discriminating TNBC between these populations. Subsequent miRNA target analysis revealed their involvement in the interconnected PI3K/AKT, MAPK and insulin signaling pathways. Additionally, three miRNAs of this panel were associated with early age at diagnosis. Altogether, these findings indicated that there are different patterns of miRNA expression between TNBC of AA and NHW women and that their mapping in genomic regions with high levels of CNAs is not merely physical, but biologically relevant to the TNBC phenotype. Once validated in distinct cohorts of AA women, this panel can potentially represent their intrinsic TNBC genome signature.