Originally published as JCO Early Release 10.1200/JCO.2008.18.5678 on January 12 2009

This Article Full Text Full Text (PDF) Data Supplements Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Reyniès, A. Articles by Bertherat, J. Search for Related Content PubMed PubMed Citation Articles by de Reyniès, A. Articles by Bertherat, J. Social Bookmarking                            What's this?

Gene Expression Profiling Reveals a New Classification of Adrenocortical Tumors and Identifies Molecular Predictors of Malignancy and Survival

Aurélien de Reyniès, Guillaume Assié, David S. Rickman, Frédérique Tissier, Lionel Groussin, Fernande René-Corail, Bertrand Dousset, Xavier Bertagna, Eric Clauser, Jérôme Bertherat

From the Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer; Institut National de la Santé et de la Recherche Médicale, Unité 567, Centre National de La Recherche Scientifique, Unité Mixte de Recherche 8104, Institut Cochin, Endocrinology, Metabolism & Cancer Department; Université Paris Descartes; Department of Endocrinology, Department of Pathology, Unit of Digestive and Endocrine Surgery, Center for Rare Adrenal Diseases, Oncogenetic Unit, Assistance Publique Hôpitaux de Paris, Hôpital Cochin; and the Rare Adrenal Cancer Network-Corticomédullosurrénale Tumeur Endocrine, Institut National du Cancer, Paris, France.

Corresponding author: Jérôme Bertherat, MD, PhD, Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 27, rue du Faubourg Saint-Jacques, 75014, Paris, France; e-mail: jerome.bertherat{at}cch.aphp.fr.

Purpose Adrenocortical tumors, especially cancers, remain challenging both for their diagnosis and prognosis assessment. The aim of this article is to identify molecular predictors of malignancy and of survival.

Patients and Methods One hundred fifty-three unilateral adrenocortical tumors were studied by microarray (n = 92) or reverse transcription quantitative polymerase chain reaction (n = 148). A two-gene predictor of malignancy was built using the disease-free survival as the end point in a training cohort (n = 47), then validated in an independent validation cohort (n = 104). The best candidate genes were selected using Cox models, and the best gene combination was validated using the log-rank test. Similarly, for malignant tumors, a two-gene predictor of survival was built using the overall survival as the end point in a training cohort (n = 23), then tested in an independent validation cohort (n = 35).

Results Unsupervised clustering analysis discriminated robustly the malignant and benign tumors, and identified two groups of malignant tumors with very different outcome. The combined expression of DLG7 and PINK1 was the best predictor of disease-free survival (log-rank P 10^–12), could overcome the uncertainties of intermediate pathological Weiss scores, and remained significant after adjustment to the Weiss score (P < 1.3 x 10^–2). Among the malignant tumors, the combined expression of BUB1B and PINK1 was the best predictor of overall survival (P < 2 x 10^–6), and remained significant after adjusting for MacFarlane staging (P < .005).

Conclusion Gene expression analysis unravels two distinct groups of adrenocortical carcinomas. The molecular predictors of malignancy and of survival are reliable and provide valuable independent information in addition to pathology and tumor staging. These original tools should provide important improvements for adrenal tumors management.

A.d.R. and G.A. contributed equally to this study.

Supported by the Ligue Nationale Contre le Cancer as part of the Cartes d'Identité des Tumeurs program and in part by the Plan Hospitalier de Recherche Clinique (AOM 02068) to the Corticomédullosurrénale, Tumeur Endocrine network chaired by P F Plouin (Université Paris-Descartes) and the Conny-Maeva foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

The Acknowledgment and Appendix are included in the full-text version of this article; they are available online at www.jco.org. They are not included in the PDF version (via Adobe® Reader®).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				L. J. Tacon, P. S. Soon, A. J. Gill, A. S. Chou, A. Clarkson, J. Botling, P. L. H. Stalberg, B. M. Skogseid, B. G. Robinson, S. B. Sidhu, et al. The Glucocorticoid Receptor Is Overexpressed in Malignant Adrenocortical Tumors J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4591 - 4599. [Abstract] [Full Text] [PDF]

				C. Laurell, D. Velazquez-Fernandez, K. Lindsten, C. Juhlin, U. Enberg, J. Geli, A. Hoog, M. Kjellman, J. Lundeberg, B. Hamberger, et al. Transcriptional profiling enables molecular classification of adrenocortical tumours Eur. J. Endocrinol., July 1, 2009; 161(1): 141 - 152. [Abstract] [Full Text] [PDF]

				E. Louiset, C. A. Stratakis, V. Perraudin, K. J. Griffin, R. Libe, S. Cabrol, B. Feve, J. Young, L. Groussin, J. Bertherat, et al. The Paradoxical Increase in Cortisol Secretion Induced by Dexamethasone in Primary Pigmented Nodular Adrenocortical Disease Involves a Glucocorticoid Receptor-Mediated Effect of Dexamethasone on Protein Kinase A Catalytic Subunits J. Clin. Endocrinol. Metab., July 1, 2009; 94(7): 2406 - 2413. [Abstract] [Full Text] [PDF]