Purpose: Adrenocortical adenomas are common, whereas adrenocortical carcinomas are rare. Discriminating between benign and malignant adrenocortical tumors using conventional histology can be difficult. In addition, adrenocortical carcinomas generally have poor prognosis and limited treatment options. MicroRNAs are short noncoding RNAs that are involved in regulation of gene transcription. Experimental Design: To identify microRNAs involved in the pathogenesis of adrenocortical tumors, expression profiling of microRNAs was done on a cohort of 22 adrenocortical carcinomas, 27 adrenocortical adenomas, and 6 normal adrenal cortices. Results: Twenty-three microRNAs were found to be significantly differentially expressed between adrenocortical carcinomas and adrenocortical adenomas. miR-335 and miR-195 were significantly downregulated in adrenocortical carcinomas compared with adrenocortical adenomas. This result was further validated in an external cohort of six adrenocortical carcinomas and four adrenocortical adenomas. Using Kaplan-Meier analysis, downregulation of miR-195 and upregulation of miR-483-5p in adrenocortical carcinomas were significantly associated with poorer disease-specific survival. Conclusions: These findings indicate that deregulation of microRNAs is a recurring event in human adrenocortical carcinomas and that aberrant expression of miR-195 and miR-483-5p identifies a subset of poorer prognosis adrenocortical carcinomas. (Clin Cancer Res 2009;15(24):7684-92)
The management of adrenocortical tumors (ACTs) is complex. The Weiss score is the present most widely used system for ACT diagnosis. An ACT is scored from 0 to 9, with a higher score correlating with increased malignancy. However, ACTs with a score of 3 can be phenotypically benign or malignant. Our objective is to use microarray profiling of a cohort of adrenocortical carcinomas (ACCs) and adrenocortical adenomas (ACAs) to identify discriminatory genes that could be used as an adjunct to the Weiss score. A cohort of Weiss score defined ACCs and ACAs were profiled using Affymetrix HGU133plus2.0 genechips. Genes with high-discriminatory power were identified by univariate and multivariate analyses and confirmed by quantitative real-time reverse transcription PCR and immunohistochemistry (IHC). The expression of IGF2, MAD2L1, and CCNB1 were significantly higher in ACCs compared with ACAs while ABLIM1, NAV3, SEPT4, and RPRM were significantly lower. Several proteins, including IGF2, MAD2L1, CCNB1, and Ki-67 had high-diagnostic accuracy in differentiating ACCs from ACAs. The best results, however, were obtained with a combination of IGF2 and Ki-67, with 96% sensitivity and 100% specificity in diagnosing ACCs. Microarray gene expression profiling accurately differentiates ACCs from ACAs. The combination of IGF2 and Ki-67 IHC is also highly accurate in distinguishing between the two groups and is particularly helpful in ACTs with Weiss score of 3.
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