Phosphodiesterase sequence variants may predispose to prostate cancer.

Endocr Relat Cancer 2015 Aug 15;22(4):519-30. Epub 2015 May 15.

Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USASchool of Health and BiosciencesPontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR 80215-901, BrazilDepartment of Pharmacology and PhysiologyGeorge Washington University, Washington, DC 20037, USALaboratory of Genomics and Molecular BiologyCIPEDepartment of PathologyA.C. Camargo Cancer Center, 01509-010 São Paulo, SP, BrazilDepartment of StatisticsGeorge Washington University, Washington, DC 20037, USA Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics (PDEGEN) and Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD 20892, USASchool of Health and BiosciencesPontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR 80215-901, BrazilDepartment of Pharmacology and PhysiologyGeorge Washington University, Washington, DC 20037, USALaboratory of Genomics and Molecular BiologyCIPEDepartment of PathologyA.C. Camargo Cancer Center, 01509-010 São Paulo, SP, BrazilDepartment of StatisticsGeorge Washington University, Washington, DC 20037, USA

We hypothesized that mutations that inactivate phosphodiesterase (PDE) activity and lead to increased cAMP and cyclic guanosine monophosphate levels may be associated with prostate cancer (PCa). We sequenced the entire PDE coding sequences in the DNA of 16 biopsy samples from PCa patients. Novel mutations were confirmed in the somatic or germline state by Sanger sequencing. Data were then compared to the 1000 Genome Project. PDE, CREB and pCREB protein expression was also studied in all samples, in both normal and abnormal tissue, by immunofluorescence. We identified three previously described PDE sequence variants that were significantly more frequent in PCa. Four novel sequence variations, one each in the PDE4B,PDE6C, PDE7B and PDE10A genes, respectively, were also found in the PCa samples. Interestingly, PDE10A and PDE4B novel variants that were present in 19 and 6% of the patients were found in the tumor tissue only. In patients carrying PDE defects, there was pCREB accumulation (P<0.001), and an increase of the pCREB:CREB ratio (patients 0.97±0.03; controls 0.52±0.03; P-value <0.001) by immunohistochemical analysis. We conclude that PDE sequence variants may play a role in the predisposition and/or progression to PCa at the germline and/or somatic state respectively.

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Source
http://dx.doi.org/10.1530/ERC-15-0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499475PMC
August 2015

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