Clinical and Pathophysiological Implications of Chromosomal Alterations in Adrenocortical Tumors: An Integrated Genomic Approach

Abstract

Diagnosing malignancy of adrenocortical tumors (ACT) and predicting prognosis in carcinomas are often challenging. Transcriptome markers have recently emerged, providing promising clinical relevance and improved pathophysiological knowledge. Whether tumoral chromosomal alterations provide similar information is not known. The aim was to evaluate the diagnostic and prognostic value of chromosomal alterations in ACT and to identify genes associated with benign and malignant tumorigenesis. Chromosomal alterations of 86 adenomas and 52 carcinomas were identified by comparative genomic hybridization arrays and/or quantitative PCR. A larger proportion of the genome is altered in carcinomas compared with adenomas (44 vs. 10%, P = 2.10(-10)). In adenomas, the 9q34 region, which includes the steroidogenic factor 1 locus, is commonly gained and associated with an overexpression of steroidogenic factor 1 (SF-1). In carcinomas, recurrent gains include chromosomes 5, 7, 12, 16, 19, and 20 and recurrent losses chromosomes 13 and 22. Filtering the genes from these regions according to their expression profile identified genes potentially relevant to adrenocortical tumorigenesis. A diagnostic tool was built by combining DNA copy number estimates at six loci (5q, 7p, 11p, 13q, 16q, and 22q). This tool discriminates carcinomas from adenomas in an independent validation cohort (sensitivity 100%, specificity 83%). In carcinomas, the number of chromosomal alterations was not associated with survival (Cox P = 0.84). A prognostic tool based on tumor DNA was designed with a clustering strategy and validated in an independent cohort. Chromosomal alterations in ACT discriminate carcinomas from adenomas and contain prognostic information. Chromosomal alterations alter the expression of genes important for tumorigenesis.