Study of molecular biomarker candidates for prognosis in clear cell renal carcinoma

Author(s)

Santiago Andrés Vilella Arias

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2013-12-17

Examining board members

Eduardo Moraes Rego Reis; Daniela Sanchez Bassères; Katia Ramos Moreira Leite; Maria Aparecida Nagai; Mari Cleide Sogayar

• Advisor: Eduardo Moraes Rego Reis

Abstract

The renal cell carcinoma (RCC) is the most aggressive tumor that affects the kidney in adult people. The RCC is a heterogeneous disease, with many different molecular alterations and varied histological and clinical patterns with different outcome. Currently, only classic anatomopathological variables are used to determine patients\' prognosis. Using a DNA microarray platform, our group identified in a previous work a set of genes differentially expressed in renal tumors. In this study, nine candidates were selected for evaluation as prognostic biomarkers in RCC. Alteration of the gene expression in RCC tumor samples was confirmed for ARNTL, ACTN4 and EPAS1 (p < 0.05) by real time PCR. Additionally, gene expression changes of ARNTL, EPAS1 and CASP7 were also observed in immortalized cell lines derived from renal tumors, recapitulating the expression changes detected in the patients\' tumors. Next, we used tissue microarrays to investigate the protein expression of the selected candidates by immunohistochemistry. Expression of the proteins ACTN4, ARNTL, CASP7 and EPAS1 was detected as significantly downregulated (p < 0.05) in patients´ tumors relative to non-tumor renal tissue. Furthermore, immunostaining patterns of the selected candidates were able to stratify patients with RCC in different risk groups according to cancer-specific survival, which also showed significant associations with anatomopathological parameters used in the clinics. ACTN4, ARNTL and EPAS1 immunostaining resulted as independent prognostic parameters of patient survival. CASP7 immunostaining was able to identify subgroups of patients with worse prognosis in a set of low risk patients as determined by their clinical stage, and also identified patients with lower risk of death from cancer amongst patients that relapsed within 5 years after surgery. Overall, these results point to a new set of molecular biomarkers with potential relevance to help in the prognosis of patients with renal cell carcinoma. (AU)