Differential RNA expression in benign and malignant adrenocortical tumours

Abstract: Adrenocortical cancer is a rare but very aggressive endocrine tumor, with a yearly incidence of 0.5 to 2 cases per million inhabitants, accounting for 0.2% of all cancer related deaths. This contrasts to the high prevalence of adrenocortical tumors up to 9%, which are detected with the increasing use of modern imaging methods such as ultrasound, computed tomography and magnetic resonance imaging. The most frequent clinical presentation is an abdominal mass without any other specific symptom. Although there are some radiological and histological features indicative of adrenocortical cancer, the diagnosis is difficult. Markers for the distinction of malignant tumors are needed. Genomic profiling tools such as cDNA microarrays have revealed transcriptional signatures, enabling to predict malignant behavior in several different neoplasms. This technique can also provide a valuable insight into the molecular mechanisms involved in cancer development and progression, to help identifying genes of potential therapeutic and diagnostic importance. The aim of the present study was to investigate the differences in the transcriptional profiles between benign and malignant adrenocortical tumors through the use of microarray technology, to further characterize these differences between hormonally producing adrenocortical tumors, incidentalomas and normal adrenocortical samples, and to find genes that can serve as potential markers for the diagnosis of adrenocortical cancer. In paper I seven patients with adrenocortical carcinomas and thirteen with adenomas were studied. Total RNA was obtained from all clinical samples. Gene expression analysis of these tumors was conducted by cDNA microarray. Transcriptional profiles were homogeneous among adenomas and heterogeneous in carcinomas. Hierarchical clustering and self-organizing maps could clearly separate carcinomas from adenomas. Among genes that were upregulated in carcinomas were two ubiquitin related genes (USP4 and UFD1L) and several insulin-like growth factor related genes (IGF2, IGF2R, IGFBP3 and IGFBP6). Among other genes that were downregulated in carcinomas were several genes related to cell metabolism (ALDH1A1, RARRES2, CYBRD1 and GSTA4), a cytokine (CXCL 10) and a cadherin 2 (CDH2). Through the use of cDNA arrays adrenocortical adenomas and carcinomas may be clearly distinguished, based on their specific molecular signature. In paper II we analyzed mRNA expression profiles in adrenocortical samples: nine hormonally active benign tumors (five cortisol and four aldosterone producing tumors), eight hormonally inactive benign tumors (incidentalomas) eight adrenocortical carcinomas and four normal adrenocortical tissue samples. Through the use of cDNA arrays, adenomas and carcinomas may be clearly distinguished based on their specific molecular signature. Several genes were identified which were expressed in different benign tumor subtypes. Identification of these differentially expressed genes may enhance our understanding of the molecular biology of adrenocortical tumor development and its functional phenotype, and may create possibilities for new diagnostic, prognostic and therapeutic tools.