title: Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer.
abstract: 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.
authors.affiliation: 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
authors.forename: Fabio Rueda
authors.initials: FR
authors.lastname: Faucz
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Anya
authors.initials: A
authors.lastname: Rothenbuhler
authors.forename: Madson Q
authors.initials: MQ
authors.lastname: Almeida
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Raffin-Sanson
authors.forename: Jerome
authors.initials: J
authors.lastname: Bertherat
authors.forename: Dirce Maria
authors.initials: DM
authors.lastname: Carraro
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.forename: Gustavo de Campos
authors.initials: Gde C
authors.lastname: Molina
authors.forename: Antonio H
authors.initials: AH
authors.lastname: Campos
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Alexandre
authors.forename: Marcelo Luiz
authors.initials: ML
authors.lastname: Bendhack
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: 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
chemical_list: D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human