ECE2017 Guided Posters Adrenal 2 (10 abstracts)
Integrated genomic and phenomic analysis reveals key molecular pathways of aldosterone producing adenoma
Fabio Fernandes-Rosa 1, , Sheerazed Boulkroun 1 , Felipe Golib Dzib 3 , Georgios Daniil 1 , Laurence Amar 1, , Bastien Rance 5 , Benoit Samson-Couterie 1 , Xavier Jeunemaitre 1, , Tchao Meatchi 1, , Arndt Benecke 7, , Tim Strom 9, & Maria-Christina Zennaro 1,
1INSERM, UMRS_970, Paris Cardiovascular Research Center, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 2Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France; 3Institut des Hautes Etudes Scientifiques, Bures sur Yvette, France; 4Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension artérielle, Paris, France; 5Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Département d’Informatique Hospitalière, Paris, France; 6Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Anatomie Pathologique, Paris, France; 7Université Pierre et Marie Curie, Paris, France; 8CNRS UMR 7224, Paris, France; 9Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; 10Institute of Human Genetics, Technische Universität München, Munich, Germany.
Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D have been described in 50% of aldosterone producing adenomas (APA). To identify genetic alterations in new genes, we performed whole exome sequencing in 23 patients with APA negative for recurrent mutations in known driver genes. A low number of somatic variations were identified per patient, ranging from 1 to 22. No somatic variations were identified in two patients. Somatic mutations in KCNJ5 and CACNA1D were identified in 12 APA. These mutations were not observed or were present at very low levels on previous Sanger sequencing, indicating tumor heterogeneity. Two patients harbored mutations in genes involved in the Wnt/β-catenin pathway, which represents, together with the membrane ion transporter activity, the two significantly overrepresented pathways in gene ontology analysis. Sequencing of CTNNB1 in somatic DNA from 150 subjects with APA identified additional variants in 13 subjects, including 2 APA harboring also a KCNJ5 mutation. Transcriptome data obtained from 123 APA and 11 control adrenals did not show differences on the expression levels of Wnt4, an activator of the Wnt/β-catenin pathway, and LEF1 and Axin2, two β-catenin target genes, as a function of the mutation status. Hierarchical clustering of transcriptional profiles at a genome-wide scale was not associated to the APA mutation status, supporting a model whereby all recurrent mutations converge upon activation of calcium signaling and increased aldosterone production. In addition, β-catenin activation was observed by immunohistochemical analysis in two thirds of APA independently of CTNNB1 mutations, suggesting the involvement of additional mechanisms promoting cell proliferation. Using transcriptome affinity-propagation-based analysis we identified 15 different clusters of APA. These clusters are not associated with demographic or clinical data, highlighting additional molecular pathways underlying APA development and identifying subgroups to be targeted for gene discovery.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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