Integrated copy number and miRNA expression analysis in triple negative breast cancer of Latin American patients
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Bruna M. Sugita1,2, Silma R. Pereira3, Rodrigo C. de Almeida4, Mandeep Gill5, Akanksha Mahajan5, Anju Duttargi5, Saurabh Kirolikar5, Paolo Fadda6, Rubens S. de Lima7, Cicero A. Urban7, Kepher Makambi8, Subha Madhavan5,9, Simina M. Boca5,8,9, Yuriy Gusev5,9, Iglenir J. Cavalli1, Enilze M.S.F. Ribeiro1 and Luciane R. Cavalli2,5
1 Department of Genetics, Federal University of Paraná, Curitiba, PR, Brazil
2 Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, PR, Brazil
3 Department of Biology, Federal University of Maranhão, São Luis, MA, Brazil
4 Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
5 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA
6 Genomics Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
7 Breast Unit, Hospital Nossa Senhora das Graças, Curitiba, PR, Brazil
8 Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University Medical Center, Washington DC, USA
9 Innovation Center for Biomedical Informatics (ICBI), Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA
|Luciane R. Cavalli,||email:||firstname.lastname@example.org|
Keywords: microRNA; triple-negative breast cancer; copy number; latinas; disparities
Received: July 11, 2019 Accepted: September 16, 2019 Published: October 22, 2019
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.
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