Endocrine Abstracts (2012) 29 P29

The ACTH-independent macronodular adrenal hyperplasia gene hunt: from candidate genes to a pangenomic strategy

G. Assié1,2, R. Libé1,2,3, A. Guimier1, S. Espiard1, F. René-Corail1, K. Perlemoine1, F. Letourneur1, X. Bertagna1,2,3, L. Groussin1,2 & J. Bertherat1,2,3


1Institut Cochin, Paris, France; 2Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France; 3Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Rare Adrenal Cancer Network COMETE-INCA, Paris, France.


ACTH-independent macronodular hyperplasia (AIMAH) affects both adrenals, and familial forms are reported, suggesting a genetic origin. Rare mutations have been reported in several genes, including Gs alpha (GNAS), Phosphodiesterase 11A (PDE11A), Fumarate Hydratase (FH), and the Glucocorticoids receptor (GR).

Objective: To assess the prevalence known genes mutations, and identify new candidate genes in AIMAH.

Design and methods: Germline and/or tumor DNA of 62 AIMAH patients was studied by direct sequencing of candidate genes (GNAS, PDE11A, FH and GR), and by pangenomic genotyping using Affymetrix SNP6 arrays in search for chromosomal alterations in germline and in AIMAH nodules.

Results: Missense PDE11A mutations were more common in patients (18/62, 29%) than in controls (7% in 279 controls). Mutations in FH were found in 4/49 patients (8%). No germline GR mutation, and no somatic GNAS mutation were found.

Chromosomal gains and losses are uncommon in AIMAH nodules; a recurrent gain was found in 1q (2/29); recurrent losses included chromosomes 1p (3/29), 3, 17 and 18q (2/29). No large recurrent gain or loss was found in germline; one loss in 6q, and in 16p, and one gain in 9q were found. Copy neutral loss of heterozygosity in chromosome 16p was found in 10 nodules from 6 out of 29 patients studied.

Conclusions: Candidate genes and pangenomic approaches are complementary methods to decipher the complexity of AIMAH genetics. PDE11A mutations seem to predispose to AIMAH. Copy neutral loss of heterozygosity in chromosome 16p is the most common alteration in AIMAH nodules, suggesting the implication of gene(s) in this region.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.

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