Phosphodiesterase 11A (<i>PDE11A</i>) Genetic Variants May Increase Susceptibility to Prostatic Cancer

Faucz, Fábio R.; Horvath, Anélia; Rothenbühler, Anya; Almeida, Madson Q.; Libé, Rossella; Raffin-Sanson, Marie Laure; Bertherat, Jérôme; Carraro, Dirce Maria; Soares, Fernando Augusto; Molina, Gustavo de Campos; Campos, Antônio Hugo José Fróes Marques; Alexandre, Rodrigo Bertollo de; Bendhack, Marcelo L.; Nesterova, Maria; Stratakis, Constantine A.

doi:10.1210/jc.2010-1655

Cited by 46 publications

(26 citation statements)

References 19 publications

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“…Our group has previously reported on the possible involvement of PDE11A in PCa pathogenesis (Faucz et al 2011). Recent findings from other groups support these observations.…”

Section: Discussionmentioning

confidence: 99%

“…It was discovered that the use of Rolipram®, a selective PDE4 inhibitor, enhances the production of cAMP/PKA and increases AR and PSA expression significantly (Sarwar et al 2014). Prostatic tissue is indeed highly sensitive to cAMP (Faucz et al 2011), and both PKA activity and cAMP levels have been associated with PCa (Chung, et al 2009; Desiniotis, et al 2010; Dimitriadis, et al 2008; Sarwar et al 2014). Our finding in this study that a novel, somatic nonsynonymous PDE4B variant (p.Asn38Lys) is present in PCa patients, may explain the down-regulation of PDE4B in PCa that has been described by others (Kashiwagi et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…While Chavez et al (2013) showed that PDE5i inhibitors may have a protective effect from PCa, studies of PDE11A inactivation suggest opposite effects in various tumor settings (Boikos, et al 2008; Faucz et al 2011; Horvath et al 2006a; Horvath et al 2006b; Horvath et al 2009; Libe, et al 2008; Libe et al 2011; Vezzosi, et al 2012). According to Faucz et al (2011), patients with PCa tended to have a higher frequency of PDE11A -inactivating variants when compared to controls (p-value < 0.001; OR = 3.81, 95%; CI = 1.86–7.81). The present work confirms these findings and also adds two significantly associated variants that are overrepresented in the PCa patients: rs79903863 (p-value ≈ 6.1*10^(-5); OR = 1.10; 95% CI = 0.98-1.23) and rs75461311 (p-value ≈ 1.4*10^(-4); OR = 26.9; 95% CI = 6.40-113).…”

Section: Discussionmentioning

confidence: 99%

“…Tadalafil®, a drug that is widely used for erectile dysfunction is, in addition to its PDE5i role, the strongest PDE11A inhibitor (Washington and Shindel 2010). PDE11A -inactivating mutations and sequence have been linked to predisposition to PCa, testicular germ cell cancer, and adrenal tumors (Faucz, et al 2011; Horvath, et al 2006a; Horvath, et al 2006b; Horvath, et al 2009; Libe, et al 2011). …”

Section: Introductionmentioning

confidence: 99%

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Phosphodiesterase sequence variants may predispose to prostate cancer

Alexandre¹,

Horvath²,

Szarek³

et al. 2015

Endocrine-Related Cancer

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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.

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“…Our group has previously reported on the possible involvement of PDE11A in PCa pathogenesis (Faucz et al 2011). Recent findings from other groups support these observations.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phosphodiesterase sequence variants may predispose to prostate cancer

Alexandre¹,

Horvath²,

Szarek³

et al. 2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

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“…Although germline PDE11A protein-truncating mutations are seen in the general population, they are significantly more common among patients with adrenal hyperplasia [22]. Mutations are frequently found in other adrenocortical tumors, testicular, and prostatic cancer [23–25]. A PDE8B missense mutation (p.H305P) was described in a young girl with isolated micron-odular adrenocortical disease (iMAD); a PDE8B knock-out mouse model was also reported with Cushing syndrome due to iMAD-like histopathology [26–28].…”

mentioning

confidence: 99%

Cyclic AMP, Protein Kinase A, and Phosphodiesterases: Proceedings of an International Workshop

Stratakis

2012

Horm Metab Res

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Cyclic nucleotides cAMP and cGMP are part of almost all major cellular signaling pathways. Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cAMP and cGMP. Protein kinase A or cAMP-dependent protein kinase mediates most cAMP effects in the cell. Over the last 25 years, various components of this group of molecules have been involved in human diseases, both genetic and acquired. Lately, the PDEs attract more attention. The pharmacological exploitation of the PDE’s ability to regulate cGMP and cAMP, and through them, a variety of signaling pathways, has led to a number of new drugs for diverse applications from the treatment of erectile dysfunction to heart failure, asthma, and chronic obstructive pulmonary disease. We present the abstracts (available online) and selected articles from the proceedings of a meeting that took place at the National Institutes of Health (NIH), Bethesda, MD, June 8–10, 2011.

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Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late‐onset cancers

Hao,

Zhao,

Fan

et al. 2023

Cancer Medicine

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BackgroundPathogenic germline variants (PGVs) can play a vital role in the oncogenesis process in carriers. Previous studies have recognized that PGVs contribute to early onset of tumorigenesis in certain cancer types, for example, colorectal cancer and breast cancer. However, the reported prevalence data of cancer‐associated PGVs were highly inconsistent due to nonuniform patient cohorts, sequencing methods, and prominent difficulties in pathogenicity interpretation of variants. In addition to the above difficulties, due to the rarity of cases, the prevalence of cancer PGV carriers in young cancer patients affected by late‐onset cancer types has not been comprehensively evaluated to date.MethodsA total of 131 young cancer patients (1–29 years old at diagnosis) were enrolled in this study. The patients were affected by six common late‐onset cancer types, namely, lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and head–neck cancer. Cancer PGVs were identified and analyzed. based on NGS‐based targeted sequencing followed by bioinformatic screening and strict further evaluations of variant pathogenicity.ResultsTwenty‐three cancer PGVs in 21 patients were identified, resulting in an overall PGV prevalence of 16.0% across the six included cancer types, which was approximately double the prevalence reported in a previous pancancer study. Nine of the 23 PGVs are novel, thus expanding the cancer PGV spectrum. Seven of the 23 (30.4%) PGVs are potential therapeutic targets of olaparib, with potential implications for clinical manipulation. Additionally, a small prevalence of somatic mutations of some classic cancer hallmark genes in young patients, in contrast to all‐age patients, was revealed.ConclusionThis study demonstrates the high prevalence of PGVs in young cancer patients with the common late‐onset cancers and the potentially significant clinical implications of cancer PGVs, the findings highlight the value of PGV screening in young patients across lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, or head–neck cancer.

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Phosphodiesterase 11A (PDE11A) Genetic Variants May Increase Susceptibility to Prostatic Cancer

Abstract: 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.

Cited by 46 publications

References 19 publications

Phosphodiesterase sequence variants may predispose to prostate cancer

Phosphodiesterase sequence variants may predispose to prostate cancer

Cyclic AMP, Protein Kinase A, and Phosphodiesterases: Proceedings of an International Workshop

Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late‐onset cancers

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