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

Isabelle Bourdeau, Sonir R. Antonini, André Lacroix, Lawrence S. Kirschner, Ludmila Matyakhina, Dominique Lorang, Steven K. Libutti, Constantine A. Stratakis

Research output: Contribution to journalArticle

94 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1575-1585
Number of pages11
JournalOncogene
Volume23
Issue number8
DOIs
StatePublished - Feb 26 2004
Externally publishedYes

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Hyperplasia
Adrenocorticotropic Hormone
Genes
Peptides
Down-Regulation
Cell Adhesion
Cell Cycle
Adrenal Cortex Neoplasms
RNA
Chromatin Assembly and Disassembly
Microarray Analysis
Adrenal Glands
Oligonucleotide Array Sequence Analysis
Vasopressins
Catecholamines
Cluster Analysis
Hydrocortisone
Proteins
Hormones
Insulin

Keywords

  • Adrenal cortex
  • Cushing syndrome
  • Genetics
  • Macronodular hyperplasia

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Bourdeau, I., Antonini, S. R., Lacroix, A., Kirschner, L. S., Matyakhina, L., Lorang, D., ... Stratakis, C. A. (2004). Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene, 23(8), 1575-1585. https://doi.org/10.1038/sj.onc.1207277

Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. / Bourdeau, Isabelle; Antonini, Sonir R.; Lacroix, André; Kirschner, Lawrence S.; Matyakhina, Ludmila; Lorang, Dominique; Libutti, Steven K.; Stratakis, Constantine A.

In: Oncogene, Vol. 23, No. 8, 26.02.2004, p. 1575-1585.

Research output: Contribution to journalArticle

Bourdeau, I, Antonini, SR, Lacroix, A, Kirschner, LS, Matyakhina, L, Lorang, D, Libutti, SK & Stratakis, CA 2004, 'Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators', Oncogene, vol. 23, no. 8, pp. 1575-1585. https://doi.org/10.1038/sj.onc.1207277
Bourdeau, Isabelle ; Antonini, Sonir R. ; Lacroix, André ; Kirschner, Lawrence S. ; Matyakhina, Ludmila ; Lorang, Dominique ; Libutti, Steven K. ; Stratakis, Constantine A. / Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. In: Oncogene. 2004 ; Vol. 23, No. 8. pp. 1575-1585.
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AB - 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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