Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors.
OBJECTIVE
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).


METHODS
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.
INSERM U567.
Rossella
R
Libé
Amato
A
Fratticci
Joel
J
Coste
Frédérique
F
Tissier
Anelia
A
Horvath
Bruno
B
Ragazzon
Fernande
F
Rene-Corail
Lionel
L
Groussin
Xavier
X
Bertagna
Marie Laure
ML
Raffin-Sanson
Constantine A
CA
Stratakis
Jérome
J
Bertherat
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D018246:Adrenocortical Adenoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism
D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human