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Phosphodiesterase 11A (PDE11A) and Genetic Predisposition to Adrenocortical Tumors

Authors' Affiliations: ¹ INSERM U567; ² Institut Cochin; ³ CNRS UMR8104; ⁴ Université Paris 5; ⁵ Department of Endocrinology, Reference Center for Rare Adrenal Diseases, ⁶ Department of Biostatistics, and ⁷ Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France; ⁸ Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland; and ⁹ Assistance Publique Hôpitaux de Paris, Hôpital Ambroise Paré, Department of Endocrinology, Boulogne sur Seine and University of Versaille, St. Quentin, France

Requests for reprints: Jérôme Bertherat, Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, Pavillon Cornil, 27, rue du Faubourg Saint-Jacques, 75014 Paris, France. Phone: 33-1-58-41-18-95; Fax: 33-1-46-33-80-60; E-mail: jerome.bertherat{at}cch.ap-hop-paris.fr.

Purpose: We have reported previously nonsense inactivating mutations of the phosphodiesterase 11A (PDE11A) gene in patients with micronodular adrenocortical hyperplasia and Cushing syndrome. The aim of this study is to investigate the presence of somatic or germ-line PDE11A mutations in various types of adrenocortical tumors: ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), adrenocortical adenoma (ACA), and adrenocortical cancer (ACC).

Experimental Design: PDE11A was sequenced in 117 adrenocortical tumors and 192 controls subjects; immunohistochemistry for PDE11A and tumor cyclic AMP levels were studied in a subgroup of adrenocortical tumors.

Results: One PDE11A inactivating mutation (R307X) was found in one ACA, 22 germ-line missense variants (18.8%) were found in adrenocortical tumors, and only 11 missense variants (5.7%) were found in controls. By comparing the common mutations, a higher frequency of mutations in adrenocortical tumors than in age/sex-matched controls were observed [16% versus 10% in ACC, 19% versus 10% in ACA, and 24% versus 9% in AIMAH; odds ratio (OR), 3.53; P = 0.05]. Somatic DNA from adrenocortical tumors with missense variants showed a wild-type allelic loss. A significant difference between ACC and controls was observed for a polymorphism in exon 6 (E421E; OR, 2.1; P = 0.03) and three associated polymorphisms located in intron 10-exon 11-intron 11 (OR, 0.5; P = 0.01). In AIMAH/ACA, cyclic AMP levels were higher than in normal adrenals and decreased PDE11A immunostaining was present in adrenocortical tumors with PDE11A variants.

Conclusions: The present investigation of a large cohort of adrenocortical tumors suggests that PDE11A sequence defects predispose to a variety of lesions (beyond micronodular adrenocortical hyperplasia) and may contribute to the development of these tumors in the general population.