Genetic alterations of phosphodiesterase 11A (PDE11A) in acromegalic patients

Erika Peverelli; Federica Ermetici; Marcello Filopanti; Andrea Lania; Stefano Ferrero; Paolo Beck-Peccoz; Anna Spada

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Endocrine Abstracts (2009) 20 P585

ECE2009 Poster Presentations Neuroendocrinology, Pituitary and Behaviour (74 abstracts)

Genetic alterations of phosphodiesterase 11A (PDE11A) in acromegalic patients

Erika Peverelli ¹ , Federica Ermetici ¹ , Marcello Filopanti ¹ , Andrea Lania ¹ , Stefano Ferrero ² , Paolo Beck-Peccoz ¹ & Anna Spada ¹

Err

Author affiliations

¹Endocrinology and Diabetology Unit, Department of Medical Sciences, University of Milan, Fondazione Ospedale Maggiore IRCCS, Milan, Italy; ²Pathology Unit, Department of Medicine, Surgery and Dentistry, Azienda Ospedaliera San Paolo e Ospedale Maggiore, Milan, Italy.

Background: Aberrant cAMP signalling is involved in the pathogenesis of somatotropinomas. Recently, variants of phosphodiesterase type 11A (PDE11A) gene have been described in patients with adrenocortical tumors. Aim of the study was to investigate the presence of these variants in patients with somatotropinomas.

Subjects and methods: Germ-line DNA of 78 acromegalic patients was screened for known genetic variants of PDE11A by direct sequencing or restriction analysis. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and in normal pituitary samples.

Results: We found non-synonymous germ-line substitutions in 17% of acromegalic patients, i.e. 14 missense variants (6 Y727C, 1 R804H, 4 R867G and 3M878V) and 1 truncating mutation in 1 patient who also presented R867G variant. Tumor DNA from these patients showed both the variant and wild-type PDE11A sequences, with the expected percentage of gsp mutations (38%). Immunohistochemistry revealed variable PDE11A expression, absence of PDE11A staining being limited to the tumor with truncating mutation. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A variants showed a tendency to have a more aggressive tumor compared to patients with wild-type sequence (extrasellar extension in 69% vs 45%).

Conclusions: This study first demonstrated the presence of nonsense/missense PDE11A variants in a subset of acromegalic patients. The retaining of the wild type allele resulting in a normal expression of the enzyme in the tumor tissues, together with the lack of significant clinical phenotype suggest that these variants might only marginally contribute to the development of somatotropinomas.