Hortense Wilmot-Roussel

Publications (3)19.49 Total impact

• Article: Identification of gene expression profiles associated with cortisol secretion in adrenocortical adenomas.

  Hortense Wilmot Roussel, Delphine Vezzosi, Marthe Rizk-Rabin, Olivia Barreau, Bruno Ragazzon, Fernande René-Corail, Aurélien de Reynies, Jérôme Bertherat, Guillaume Assié
  [show abstract] [hide abstract]
  ABSTRACT: Context:The cortisol secretion of adrenocortical adenomas can be either subtle or overt. The mechanisms leading to the autonomous hypersecretion of cortisol are unknown.Objective:To identify the gene expression profile associated with the autonomous and excessive cortisol secretion of adrenocortical adenomas.Patients and Methods:The transcriptome of 22 unilateral adrenocortical adenomas (5 non-secreting, 6 subclinical cortisol producing, 11 cortisol producing) was studied and correlated with cortisol secretion. Phosphodiesterase 8B (PDE8B) expression was measured by Western Blot.ResultsUnsupervised clustering identified two groups of adenomas with a difference in secretion level (p=0.008). Cluster 1 included only cortisol producing adenomas (8 out of 11), while Cluster 2 was an admixture of the non-secreting, the subclinical cortisol-secreting and 3 of the 11 cortisol-secreting adenomas (Fisher exact p=0.002). This cluster was driven by genes related to cortisol secretion and to extracellular matrix.More than three thousand genes correlated with cortisol secretion. Among the positively correlated were the steroidogenic enzymes, genes involved in cholesterol metabolism and glutathione S-transferases. Among the negatively correlated genes were genes related to transcripts translation and the transcription factor GATA-6.The PDE8B, which inactivates the PKA pathway, unexpectedly showed the strongest positive correlation with cortisol secretion, confirmed by Western Blot. The PKA-activity/cAMP ratio was increased in adenomas with high PDE8B levels, suggesting counter-regulation to limit downstream activation of the pathway.Conclusion:The transcriptome of adrenocortical adenomas reveals a major association with cortisol secretion and identifies specific groups of genes implicated in steroid secretion, suggesting that cAMP signalling alterations might be frequent in cortisol secreting adenomas.
  The Journal of clinical endocrinology and metabolism 03/2013; · 6.50 Impact Factor
• Article: Identification of a CpG Island Methylator Phenotype in Adrenocortical Carcinomas.

  Olivia Barreau, Guillaume Assié, Hortense Wilmot-Roussel, Bruno Ragazzon, Camille Baudry, Karine Perlemoine, Fernande René-Corail, Xavier Bertagna, Bertrand Dousset, Nadim Hamzaoui, Frédérique Tissier, Aurélien de Reynies, Jérôme Bertherat
  [show abstract] [hide abstract]
  ABSTRACT: Purpose:DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression.Experimental Design:Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium HumanMethylation27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors.Results:Methylation was higher in carcinomas than in adenomas (t test P = 3.1 × 10(-9)). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2).Conclusions:This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes.
  The Journal of clinical endocrinology and metabolism 10/2012; · 6.50 Impact Factor
• Article: Clinical and pathophysiological implications of chromosomal alterations in adrenocortical tumors: an integrated genomic approach.

  Olivia Barreau, Aurélien de Reynies, Hortense Wilmot-Roussel, Marine Guillaud-Bataille, Colette Auzan, Fernande René-Corail, Frédérique Tissier, Bertrand Dousset, Xavier Bertagna, Jérôme Bertherat, Eric Clauser, Guillaume Assié
  [show abstract] [hide abstract]
  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.
  The Journal of clinical endocrinology and metabolism 11/2011; 97(2):E301-11. · 6.50 Impact Factor