Low DICER1 expression is associated with poor clinical outcome in adrenocortical carcinoma.

Gabriela Resende Vieira De Sousa,Maria Claudia N Zerbini,Alda Wakamatsu,Beatriz M.P Mariani,Madson Q Almeida,Tamaya C Ribeiro,Maria Candida B.V Fragoso,Antonio M Lerario,Andre M Faria,Berenice B Mendonca,Ana Claudia Latronico,Venancio A.F Alves,Iberê C Soares

doi:10.18632/oncotarget.4261

Abstract

Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas.

Highlights

Adrenocortical carcinoma (ACC) is a rare neoplasia with an estimated incidence of 0.5–2.0/million/year in adults [1, 2]
DICER1 gene overexpression was more frequent in ACCs (60%, 15 out of 25) than in www.impactjournals.com/oncotarget
In order to investigate the reason for the higher frequency o DICER1 overexpression in ACCs than in adenomas, we evaluated the expression of miR-103 and miR-107 in adrenocortical adenomas and ACCs

Summary

Introduction

Adrenocortical carcinoma (ACC) is a rare neoplasia with an estimated incidence of 0.5–2.0/million/year in adults [1, 2]. MiRNA expression profile of human tumors has been characterized by an overall miRNA downregulation [7, 8]. Several studies demonstrated the potential of miRNA profiling in differentiating between adrenocortical adenomas and carcinomas, risk stratification and prognosis [9]. Little is known about posttranscriptional regulation of www.impactjournals.com/oncotarget miRNAs. We have recently demonstrated that expression of LIN28, a highly conserved RNA-binding protein that has emerged as a modulator of the processing of let-7, was associated with recurrence in ACCs [10]. Overexpression of mir-9, a negative LIN28A regulator, was a significant predictor of poor outcome in ACC patients [10]

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