Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators

Abstract

Corticotropin (ACTH)-independent macronodular adrenal hyperplasia (AIMAH) is a heterogeneous condition in which cortisol secretion may be mediated by gastrointestinal peptide (GIP), vasopressin, catecholamines and other hormones. We studied the expression profile of AIMAH by genomic cDNA microarray analysis. Total RNA was extracted from eight tissues (three GIP-dependent) and compared to total RNA obtained from adrenal glands from 62 normal subjects. Genes had to be altered in 75% of the patients, and be up-or downregulated at a cutoff ratio of at least 2.0; 82 and 31 genes were found to be consistently up-and downregulated, respectively. Among the former were regulators of transcription, chromatin remodeling, and cell cycle and adhesion. Downregulated sequences included genes involved in immune responses and insulin signaling. Hierarchical clustering correlated with the two main AIMAH diagnostic groups: GIPdependent and non-GIP-dependent. The genes encoding the 7B2 protein (SGNE1) and WNT1-inducible signaling pathway protein 2 (WISP2) were specifically overexpressed in the GIP-dependent AIMAH. For these, and six more genes, the data were validated by semiquantitative amplification in samples from a total of 32 patients (the original eight, six more cases of AIMAH, and 18 other adrenocortical hyperplasias and tumors) and the H295R adrenocortical cancer cell line. In conclusion, our data confirmed AIMAH's clinical heterogeneity by identifying molecularly distinct diagnostic subgroups. Several candidate genes that may be responsible for AIMAH formation and/or progression were also identified, suggesting pathways that affect the cell cycle, adhesion and transcription as possible mediators of adrenocortical hyperplasia.

Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors

“…They identified two clusters of genes, the IGF2 cluster and the steroidogenesis cluster, which, in combination, provide a good predictor of malignancy. As in our studies, they also confirmed the finding from the earlier analysis by Giordano et al (19) demonstrating upregulation of IGF2 expression (30). Adrenal hyperplasia was analyzed in a similar fashion by Bourdeau et al (30).…”

“…During the course of our studies, three other groups performed similar analyses of adrenocortical tissue (19,30,31). In the search for reliable markers for the clinical management of adrenal tumors, de Fraipont et al (31) designed an adrenal-specific microarray.…”

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

“…It is well known by pathologists that follicular adenomas contain few lymphocytes and this decrease has been previously reported (Aust et al, 2001). A similar reduction has been described in the thyroids of Tg-A2aR mice (Goffard et al, 2004) and in the corresponding human adrenal disease, adrenal hyperplasia (Bourdeau et al, 2004). Decreased complement expression (C1s) extends this conclusion to macrophages.…”

A case of ACTH-independent macronodular adrenal hyperplasia associated with multiple endocrine neoplasia type 1

“…According to another study on 33 patients from a single and large kindred of MEN1 (known as Tasman1), 2 The incidence of food-or GIP-dependent AIMAH is comparatively rare and has not been reported in familial cases of AIMAH [4][5][6]. In a microarray study of several types of AIMAH, analysis of gene expression profiles by hierarchical clustering revealed a distinct gene expression pattern in GIP-dependent AIMAH, which was different from that of non-GIP AIMAH [22]. This observation suggests that GIP-dependent AIMAH is fundamentally different from non-GIP AIMAH.…”