Phosphodiesterase sequence variants may predispose to prostate cancer

Abstract

We hypothesized that mutations that inactivate phosphodiesterase (PDE) activity and lead to increased cyclic AMP (cAMP) and cyclic GMP (cGMP) 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 3 previously described PDE sequence variants that were significantly higher 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, respectively, 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. Larger such studies are needed to confirm these findings.

Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco‐induced lung cancer

“… have reported that PDE10A mutations are predicted to influence PDE10A allosteric regulation in lung adenocarcinoma; that high levels of PDE10A expression correlate with worsened lung adenocarcinoma prognosis; and that Pf‐2545920 also suppresses the growth of NSCLC cell lines. Finally, PDE10A somatic mutations have been described in up to 19% of prostate cancers and correlated with increased levels of phosphorylated C‐AMP responsive element binding protein (p‐CREB) . These data suggest that PDE10A might be a relevant target for cancer therapy and prevention.…”

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

“…A high frequency of PDE variants was observed in patients with prostate cancer [31]. The pCREB:CREB ratio (phosphorylated cAMP response element-binding protein: cAMP response elementbinding protein) showed an imbalance in the cAMP availability, probably due to downregulation of some of the PDE molecules [31].…”

“…A high frequency of PDE variants was observed in patients with prostate cancer [31]. The pCREB:CREB ratio (phosphorylated cAMP response element-binding protein: cAMP response elementbinding protein) showed an imbalance in the cAMP availability, probably due to downregulation of some of the PDE molecules [31]. In the present work, when the transcriptome analysis was accessed, a decrease of PDE2A, PDE5A, and PDE8A expression and a significant overexpression of PDE4B and PDE8B was observed in adrenocortical tumors, compared to normal adrenal tissue.…”

The conserved protective cyclic AMP-phosphodiesterase function PDE4B is expressed in the adenoma and adjacent normal colonic epithelium of mammals and silenced in colorectal cancer

“…Its role in cancer is context dependent, as the cellular effect of a cAMP signal depends on the cell type and subcellular localization of the signal [ 36 , 38 ]. In the select cases in which cAMP has been shown to be oncogenic [ 39 ], it may act directly on protein kinase A (PKA) or indirectly on its downstream effectors, cAMP-responsive element binding protein and Rap Guanine Nucleotide Exchange Factor 3 (RAPGEF3) [ 40 ].…”