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

Oncogene volume 23, pages 1575–1585 (2004)Cite this article

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: GIP-dependent 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.

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Acknowledgements

The authors wish to thank the physicians who referred the patients, the nursing staff for conducting the endocrine investigation, and the patients and their families. We also thank Dr William E Farrell (Keele University, UK) for his critical review of the manuscript and useful suggestions. Isabelle Bourdeau was a fellow of the Fonds de la recherche en santé du Québec, and this work was supported in part by Grant MT-13189 from the Canadian Institutes of Health Research.

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Author notes

  1. Lawrence S Kirschner

    Present address: Ohio State University Cancer Research Center, Columbus, OH, USA

  2. Constantine A Stratakis: This work was presented in part at the 83rd Annual Meeting of The Endocrine Society, San Francisco, June 2002

Authors and Affiliations

  1. Section on Endocrinology & Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA

    Isabelle Bourdeau, Lawrence S Kirschner, Ludmila Matyakhina & Constantine A Stratakis

  2. Endocrinology Division, Hôtel-Dieu du CHUM, Montréal, Québec, Canada

    Isabelle Bourdeau, Sonir R Antonini & André Lacroix

  3. Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, 20892-1502, MD, USA

    Dominique Lorang & Steven K Libutti

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Correspondence to Constantine A Stratakis.

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Bourdeau, I., Antonini, S., Lacroix, A. et al. Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene 23, 1575–1585 (2004). https://doi.org/10.1038/sj.onc.1207277

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