Researcher Contact
Jérôme BertheratUnité Inserm 1016 "Institut Cochin" (Inserm – CNRS – Université Paris Descartes)
Responsable de l'équipe "Génomique et signalisation des tumeurs endocrines"
wrebzr.oregureng@ppu.ncuc.se
Adrenocortical carcinoma (also known as adrenal cortex cancer or ACC), is a generally aggressive tumour, with a mean survival rate of less than five years for those affected. Apart from metastasis, it exposes the patients to manifestations such as high blood pressure, diabetes, decreased potassium level, infections, etc. There is, however, some patient-dependent variation in tumour development. The team led by Prof. Bertherat at the Cochin Institute (Inserm – CNRS – Paris Descartes University) and the Expert Centre for Rare Adrenal Cancers at Cochin Hospital (AP-HP) has just published a molecular classification for this cancer in the journal Nature Genetics. The researchers identify many molecular abnormalities in these cancers that have not been well known until now, and thus reveal a new classification for these tumours.
This work involved 130 adrenocortical carcinomas, bringing together an initial cohort of some fifty tumour samples collected in the national research network COMETE (COrtico et MEdullosurrénale, Tumeurs Endocrines; COrtical and MEdullary adrenal Endocrine Tumours) and a second cohort of approximately 80 samples, collected within the European research network ENSAT (European Network for the Study of Adrenal Tumors). The complete genomes of these tumours were analysed by a combination of several high throughput genomic techniques, i.e. complete sequencing; study of the expression levels of all genes (transcriptomics) and of micro-RNAs (miRNAs); study of genetic variants (SNPs) and of gene methylation levels (epigenetics).
This study revealed the existence of two molecular types of adrenocortical carcinomas, one showing a relatively favourable prognosis for patients following complete surgery, and another for which the prognosis is unfavourable.
These two molecular types correspond to two different diseases. The type associated with a poor prognosis is characterised by a higher level of mutations, including recurrent alterations in a small group of genes already known to be involved in adrenocortical carcinoma (CTNNB1,TP53, CDKN2A, RB1, MEN1), or new genes (ZNRF3, DAXX, TERT, and MED12). In this study, ZNFR3 is specifically identified as a new tumour suppressor gene.
Moreover, specific profiles that distinguish these two cancer groups are shown by each of the following molecular analyses: gene and miRNA expression profiles, and pattern of methylation abnormalities.
This work opens up new clinical opportunities in the short term, especially in terms of predicting tumour prognosis following surgery on the lesion, and the possibility of conducting clinical studies according to tumour type. In the longer term, the research team suggests that results will allow identification of therapeutic targets specific for each of the subgroups. It is a further step in the development of a specific personalised medicine for rare cancers.
The researchers also anticipate new applications for these discoveries, especially applications based on the newly identified tumour suppressor gene ZNFR3.
Finally, the authors of the study emphasise the power of genomic methods and the importance of national and international multidisciplinary and multi-centre research networks, especially in the area of rare tumours.
This project has been developed in partnership with the French National Cancer League for several years, under the Cartes d’Identité des Tumeurs (Tumour Identity Card) programme.
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Unité Inserm 1016 "Institut Cochin" (Inserm – CNRS – Université Paris Descartes)
Responsable de l'équipe "Génomique et signalisation des tumeurs endocrines"
wrebzr.oregureng@ppu.ncuc.se
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Integrated genomic characterization of adrenocortical carcinoma
Guillaume Assié1–4,22, Eric Letouzé5,22, Martin Fassnacht6–8, Anne Jouinot1–3, Windy Luscap1–3, Olivia Barreau1–4, Hanin Omeiri1–3, Stéphanie Rodriguez1–3, Karine Perlemoine1–3, Fernande René-Corail1–3, Nabila Elarouci5, Silviu Sbiera6,7, Matthias Kroiss8, Bruno Allolio7, Jens Waldmann9, Marcus Quinkler10, Massimo Mannelli11, Franco Mantero12, Thomas Papathomas13, Ronald De Krijger13, Antoine Tabarin14,15, Véronique Kerlan15,16, Eric Baudin15,17, Frédérique Tissier1–3,18, Bertrand Dousset1–4,19, Lionel Groussin1–4, Laurence Amar20, Eric Clauser21, Xavier Bertagna1–4,15, Bruno Ragazzon1–3, Felix Beuschlein6, Rossella Libé1–4,15, Aurélien de Reyniès5,23 & Jérôme Bertherat1–4,15,23 1.
INSERM U1016, Institut Cochin, Paris, France. 2. CNRS UMR 8104, Paris, France. 3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 4. Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France. 5. Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France. 6. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, University of Munich, Munich, Germany. 7. Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany. 8. Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany. 9. Visceral, Thoracic and Vascular Surgery, University Hospital Giessen and Marburg, Marburg, Germany. 10. Department of Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine, Berlin, Germany. 11. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. 12. Endocrinology Unit, Department of Medicine, University of Padova, Padova, Italy. 13. Department of Pathology, Josephine Nefkens Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 14. Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Bordeaux, Bordeaux, France. 15. Rare Adrenal Cancer Network COMETE, Paris, France. 16. Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Brest, Brest, France. 17. Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Université Paris–Sud, Villejuif, France. 18. Department of Pathology, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Pierre et Marie Curie Université, Paris, France. 19. Department of Digestive and Endocrine Surgery, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France. 20. Hypertension Unit, Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 21. Department of Oncogenetics, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France. 22. These authors contributed equally to this work. 23. These authors jointly directed this work.
Nature Genetics, 20 avril 2014, Doi : 10.1038/ng.2953
Guillaume Assié1–4,22, Eric Letouzé5,22, Martin Fassnacht6–8, Anne Jouinot1–3, Windy Luscap1–3, Olivia Barreau1–4, Hanin Omeiri1–3, Stéphanie Rodriguez1–3, Karine Perlemoine1–3, Fernande René-Corail1–3, Nabila Elarouci5, Silviu Sbiera6,7, Matthias Kroiss8, Bruno Allolio7, Jens Waldmann9, Marcus Quinkler10, Massimo Mannelli11, Franco Mantero12, Thomas Papathomas13, Ronald De Krijger13, Antoine Tabarin14,15, Véronique Kerlan15,16, Eric Baudin15,17, Frédérique Tissier1–3,18, Bertrand Dousset1–4,19, Lionel Groussin1–4, Laurence Amar20, Eric Clauser21, Xavier Bertagna1–4,15, Bruno Ragazzon1–3, Felix Beuschlein6, Rossella Libé1–4,15, Aurélien de Reyniès5,23 & Jérôme Bertherat1–4,15,23 1.
INSERM U1016, Institut Cochin, Paris, France. 2. CNRS UMR 8104, Paris, France. 3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 4. Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France. 5. Programme Cartes d’Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France. 6. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, University of Munich, Munich, Germany. 7. Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany. 8. Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany. 9. Visceral, Thoracic and Vascular Surgery, University Hospital Giessen and Marburg, Marburg, Germany. 10. Department of Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine, Berlin, Germany. 11. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. 12. Endocrinology Unit, Department of Medicine, University of Padova, Padova, Italy. 13. Department of Pathology, Josephine Nefkens Institute, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 14. Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Bordeaux, Bordeaux, France. 15. Rare Adrenal Cancer Network COMETE, Paris, France. 16. Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Brest, Brest, France. 17. Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Université Paris–Sud, Villejuif, France. 18. Department of Pathology, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Pierre et Marie Curie Université, Paris, France. 19. Department of Digestive and Endocrine Surgery, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France. 20. Hypertension Unit, Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 21. Department of Oncogenetics, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Paris, France. 22. These authors contributed equally to this work. 23. These authors jointly directed this work.
Nature Genetics, 20 avril 2014, Doi : 10.1038/ng.2953