Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer.
BACKGROUND
Among the genomic loci harboring potential candidate genes for prostatic cancer (PCa) is the 2q31-33 chromosomal region that harbors the gene encoding phosphodiesterase 11A (PDE11A). In addition, the combined cancer genome expression metaanalysis datasets included PDE11A among the top 1% down-regulated genes in PCa.


OBJECTIVE
In the present study, we screened 50 unrelated PCa patients of Brazilian descent for PDE11A coding defects.


METHODS
The study consisted of PDE11A sequencing, in vitro functional assays, and immunostaining analysis.


RESULTS
We identified eight different sequence alterations in 15 patients (30%): one stop-codon and seven missense mutations. Three of the variants (R202C, Y658C, and E840K) were novel, and the remaining five (Y727C, R804H, R867G, M878V, and R307X) have been associated with predisposition to adrenal or testicular tumors. The overall prevalence of PDE11A-inactivating sequence variants among PCa patients was significantly higher than in 287 healthy controls (0.16 vs. 0.051, respectively, P < 0.001, odds ratio 3.81, 95% confidence interval 1.86-7.81) and the R202C, Y658C, and E840K substitutions were not found in controls. All missense mutations led to decreased PDE11A activity in human embryonic kidney 293 and PC3M cells and immunostaining of PCa samples with sequence changes showed decreased PDE11A protein expression.


CONCLUSIONS
Our data suggest that, like in the adrenal cortex and the testicular germ cells, PDE11A-inactivating genetic alterations may play a role in susceptibility to PCa.
Faucz
Fabio Rueda
FR
Section of Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA. fabio.faucz@pucpr.br
Horvath
Anelia
A
Rothenbuhler
Anya
A
Almeida
Madson Q
MQ
Libé
Rossella
R
Raffin-Sanson
Marie-Laure
ML
Bertherat
Jerome
J
Carraro
Dirce Maria
DM
Soares
Fernando Augusto
FA
Molina
Gustavo de Campos
Gde C
Campos
Antonio H
AH
Alexandre
Rodrigo B
RB
Bendhack
Marcelo Luiz
ML
Nesterova
Maria
M
Stratakis
Constantine A
CA
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D001938:Brazil; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism
D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human