PDE11A, a dual-specificity phosphodiesterase that is frequently polymorphic in the general population and conveys risk to adrenal and testicular tumors, may also be a susceptibility gene for prostatic cancer. F. R. Faucz1,2, A. Horvath1, A. Rothenbuhler1,3, D. M. Carraro4, R. B. Alexandre2, M. Nesterova1, C. A. Stratakis1 1) Section on Endocrinology & Gen, PDEGEN, NICHD, NIH, Bethesda, MD, USA; 2) Laboratory of Molecular Genetics, NIMA, PPGCS, Pontificia Universidade Catolica do Parana, Curitiba, Brazil; 3) Pediatric Endocrinology Unit, Groupe Hospitalier Cochin-Saint Vicent de Paul, Paris Descartes University, Paris, France; 4) Laboratory of Genomics and Molecular Biology - A.C. Camargo Hospital, São Paulo, Brazil.

   Despite significant advances in molecular genotyping, Prostate cancer (PC) does not appear to have a major single gene responsible for the disease. Among the genomic loci that have been suggested to harbor potential candidate genes is the 2q31-35 chromosomal area. The gene encoding phosphodiesterase 11A (PDE11A) is located on 2q31-32; it belongs to the family of phosphodiesterases (PDE)-enzymes that catalyze the hydrolysis of the second messengers cAMP and cGMP. Four different isoforms are known for PDE11A: PDE11A4 is the isoform with the highest expression in prostate, compared to all other studied endocrine tissues. We recently reported PDE11A-inactivating mutations to be associated with a predisposition to endocrine neoplasm, including adrenocortical (ADT) and testicular germ-cell tumors (TGCT), which also express the PDE11A4. In the present study we screened 50 unrelated PC patients of Brazilian descent for PDE11A sequence defects. We identified 8 different coding alterations in a total of 16 patients (32%): 7 missense and one stop-codon mutation. Three of the missense were novel (R202C, Y658C and E840K); constructs containing the mutations were tested in vitro in HEK293 human cells. All mutant transfectants impaired the ability of the protein to degrade cAMP in vitro; an additional four mutants (Y727C, R804H, R867G and M878V) and the R307X stop-codon mutation that had also been found in association with ADT and TGCT, have been tested and published elsewhere as impairing the ability of the enzyme to mediate PDE activity. We compared the type of the mutations and their frequencies with those in 287 healthy control individuals: the newly identified substitutions were not found in the control group and a significantly higher number of PDE11A missense and nonsense variations were seen in the PC patients (allelic frequency 0.16 vs 0.043 in the controls, 2=18.23, p0.0001, OR=4.18, 95%CI 2.14 - 8.16). Immunostaining and additional genetic studies aim at further clarifying the role of these sequence changes in PC. We conclude that these preliminary data point to PDE11A genetic changes as a potential susceptibility factor for PC; this is consistent with PDE11As essential role in the regulation of cAMP signaling responses in other endocrine tissues and its involvement as a risk factor for ADT and TGCT. Interestingly, PDE11A is inhibited by some of the PDE-inhibitors used for erectile dysfunction by patients of the same age as those that are at risk for PC.