Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome Profiling

Abstract

Purpose: Our understanding of adrenocortical carcinoma (ACC) has improved considerably, yet many unanswered questions remain. For instance, can molecular subtypes of ACC be identified?If so, what is their underlying pathogenetic basis and do they possess clinical significance? Experimental Design: We did a whole genome gene expression study of a large cohort of adrenocortical tissues annotated with clinicopathologic data. Using Affymetrix Human Genome U133 Plus 2.0 oligonucleotide arrays, transcriptional profiles were generated for10 normal adrenal cortices (NC), 22 adrenocortical adenomas (ACA), and 33 ACCs. Results: The overall classification of adrenocortical tumors was recapitulated using principal component analysis of the entire data set. The NC and ACA cohorts showed little intragroup variation, whereas the ACC cohort revealed much greater variation in gene expression. A robust list of 2,875 differentially expressed genes in ACC compared with both NC and ACA was generated and used in functional enrichment analysis to find pathways and attributes of biological significance. Cluster analysis of the ACCs revealed two subtypes that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. Kaplan-Meier analysis of these ACC clusters showed a significant difference in survival (P < 0.020). Multivariate Cox modeling using stage, mitotic rate, and gene expression data as measured by the first principal component for ACC samples showed that gene expression data contains significant independent prognostic information (P < 0.017).Conclusions: This study lays the foundation for the molecular classification and prognostication of adrenocortical tumors and also provides a rich source of potential diagnostic and prognostic markers.

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

“…Giordano et al (2009) Whereas several findings support the relevance of cell cycle damage in adrenocortical tumorigenesis, no data have been published on the involvement of retinoic acid signalling to date. Here, we discuss the findings established by our meta-analysis and experimental CGH-transcriptomics study and present a review of these and previous observations.…”

“…By statistical analysis of microarray studies performed by Giordano et al (2009) and To¨mbo¨l et al (2009), we have identified 554 and 450 significant gene expression changes between NAs and ACAs, respectively: 46 of these were common. In the same studies, 2509 and 2564 significant gene expression changes between NAs and ACCs were found and 1017 of these were common.…”

“…Common significant gene expression changes in the studies of Giordano et al, (2009) andTo¨mbo¨l et al, (2009) Table 2). …”

“…Overexpression G1 cyclins (cyclin E), and G1 cell division protein kinases (CDK2, CDK4) was reported in sporadic ACCs (Bourcigaux et al, 2000). Overexpression of CCNE1 and CCNE2 was found in four of the investigated microarray studies (Giordano et al, 2003(Giordano et al, , 2009To¨mbo¨l et al, 2009;de Reynie`s et al, 2009). GSEA of microarray studies revealed significant enrichment of overexpressed genes on chr19q12, where CCNE1 is mapped (Giordano et al, 2009;To¨mbo¨l et al, 2009;de Reynie`s et al, 2009).…”

“…It is of interest to note that C-MYC overexpressed in several other tumours was found to be underexpressed in three microarray data sets analysed (Giordano et al, 2009;To¨mbo¨l et al, 2009;de Reynie`s et al, 2009). In our direct comparison of CGH and GSEA results, its underexpression was correlated with loss of chr8q24, where C-MYC is harboured.…”