Abstract 3464: Prognostic value of DICER1 expression in adrenocortical cancer patients

Abstract

Abstract Deregulation of microRNA (miRNA) expression in adrenocortical carcinomas (ACCs) has important prognostic and therapeutic implications. DICER1, an endoribonuclease in the RNase III family, is a key component of the miRNA processing machinery. In cooperation with its cofactor, transactivation response (TAR) RNA-binding protein (TRBP2), DICER1 cuts the pre-miRNA to meet the specification. Low DICER1 expression was associated with poor clinical outcome in ovarian, breast and lung cancer. Recently, DICER1 mutations in the RNase IIIb domain were found in steroidogenic Sertoli-Leydig cell and embryonic tumors. In this study, we assessed the mRNA and/or protein expression of DICER1 and TARBP2 in adult adrenocortical tumors (ACTs). Additionally, we investigated DICER1 and TARBP2 hot spot mutations. Expression of miRNAs (miR-103, miR-107 and miR-497) involved in DICER1 and TARBP2 regulation was also determined. DICER1 protein expression was analyzed in 151 adult ACTs (77 adenomas and 74 carcinomas). Messenger DICER1 and TARBP2 expression was assessed in 55 ACTs (30 adenomas and 25 carcinomas) by quantitative real-time PCR. Expression of miR-103, miR-107 and miR-497 was determined in the same cohort. In addition, we sequenced four metal-binding sites (codons 1709 and 1705 in exon 24; codons 1810 and 1813 in exon 25) within the RNase IIIb catalytic center of DICER1 gene, and the (C)5 coding microsatellite repeat of exon 5 of TARBP2 gene in 61 ACTs. Low DICER1 protein expression was significantly associated with reduced overall (p = 0.01) and disease-free survival (p = 0.01) in ACC patients. Among ACC patients with stage 3 or 4, 22 out of 32 (69%) displayed low DICER1 protein expression (X2 = 10.1, p = 0.01). DICER1 protein expression was not significantly different between adenomas and carcinomas. At mRNA level, DICER1 expression had an important superposition between adenomas and carcinomas, but it was higher in carcinomas than in adenomas [median (range); 1.96 (-1.4 to 4.54) vs. 0.81 (-1.5 to 99) respectively, p = 0.03]. Among ACC patients, DICER1 mRNA levels did not predict outcome. TARBP2 expression was not associated with histological and clinical parameters. In addition, expression of miR-103, miR-107 and miR-497 did not correlate with DICER1 and TARBP2 expression in ACTs. No variant was identified in the hot spot mutation region of DICER1 and TARBP2 genes. In conclusion, DICER1 expression was significantly associated with poor outcome in adult ACC patients. However, DICER1 deregulation in ACCs was not caused by mutations within the RNase IIIb domain and not associated with expression of its regulatory miRNAs. Support: FAPESP (2012/21272-6; 2013/09621-8) Note: This abstract was not presented at the meeting. Citation Format: Gabriela Resende V de Sousa, Tamaya C. Ribeiro, André M. Faria, Beatriz MP Mariani, Antonio M. Lerario, Ibere C. Soares, Maria Claudia N. Zerbini, Alda Wakamatsu, Venancio AF Alves, Berenice B. Mendonca, Maria Candida BV Fragoso, Ana Claudia Latronico, Madson Almeida. Prognostic value of DICER1 expression in adrenocortical cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3464. doi:10.1158/1538-7445.AM2015-3464