Somatic Copy Number Alterations and Associated Genes in Clear-Cell Renal-Cell Carcinoma in Brazilian Patients

• Main Authors: Flávia Gonçalves Fernandes, Henrique Cesar Santejo Silveira, João Neif Antonio Júnior, Rosana Antunes da Silveira, Luis Eduardo Zucca, Flavio Mavignier Cárcano, André Octavio Nicolau Sanches, Luciano Neder, Cristovam Scapulatempo-Neto, Sergio Vicente Serrano, Eric Jonasch, Rui Manuel Reis, Adriane Feijó Evangelista
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: International Journal of Molecular Sciences
• Subjects: copy number aberrations; clear-cell renal-cell carcinoma; bioinformatics; Brazilian population
• Online Access: https://www.mdpi.com/1422-0067/22/5/2265
• ISSN: 1661-6596; 1422-0067

Somatic copy number aberrations (CNAs) have been associated with clear-cell renal carcinoma (ccRCC) pathogenesis and are a potential source of new diagnostic, prognostic and therapeutic biomarkers. Recurrent CNAs include loss of chromosome arms 3p, 14q, 9p, and gains of 5q and 8q. Some of these regional CNAs are suspected of altering gene expression and could influence clinical outcomes. Despite many studies of CNAs in RCC, there are currently no descriptions of genomic copy number alterations in a Brazilian ccRCC cohort. This study was designed to evaluate the chromosomal profile of CNAs in Brazilian ccRCC tumors and explore clinical associations. A total of 92 ccRCC Brazilian patients that underwent nephrectomy at Barretos Cancer Hospital were analyzed for CNAs by array comparative genomic hybridization. Most patients in the cohort had early-stage localized disease. The most significant alterations were loss of 3p (87.3%), 14q (35.8%), 6q (29.3%), 9p (28.6%) and 10q (25.0%), and gains of 5q (59.7%), 7p (29.3%) and 16q (20.6%). Bioinformatics analysis revealed 19 genes mapping to CNA significant regions, including <i>SETD2</i>, <i>BAP1</i>, <i>FLT4</i>, <i>PTEN</i>, <i>FGFR4</i> and <i>NSD1</i>. Moreover, gain of 5q34-q35.3 (<i>FLT4</i> and <i>NSD1</i>) and loss of 6q23.2-q23.3 (<i>MYB</i>) and 9p21.3 (<i>MLLT3</i>) had gene expression levels that correlated with TCGA data and was also associated with advanced disease features, such as larger tumors, Fuhrman 3, metastasis at diagnosis and death. The loss of region 14q22.1 which encompasses the <i>NIN</i> gene was associated with poor overall survival. Overall, this study provides the first CNA landscape of Brazilian patients and pinpoints genomic regions and specific genes worthy of more detailed investigations. Our results highlight important genes that are associated with copy number changes involving large chromosomal regions that are potentially related to ccRCC tumorigenesis and disease biology for future clinical investigations.