Mutations of the PDE5A Gene Confer a Survival Advantage in Patients with Colon Cancer

Lehrer, Steven F.; Rheinstein, Peter H.; Rosenzweig, Kenneth E.

doi:10.1158/1940-6207.capr-18-0105

Cited by 7 publications

(6 citation statements)

References 2 publications

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“…PDE5A plays an essential role in signal transduction by regulating the intracellular concentration of cyclic nucleotides ( 35 ). Mutation of the PDE5A gene confers a survival advantage in patients with CRC ( 36 ). KEL is a zinc endopeptidase with endothelin-3-converting enzyme activity ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia

et al. 2021

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BackgroundPatient participation in colorectal cancer (CRC) screening via a stool test and colonoscopy is suboptimal, but participation can be improved by the development of a blood test. However, the suboptimal detection abilities of blood tests for advanced neoplasia, including advanced adenoma (AA) and CRC, limit their application. We aimed to investigate the proteomic landscape of small extracellular vesicles (sEVs) from the serum of patients with colorectal neoplasia and identify specific sEV proteins that could serve as biomarkers for early diagnosis.Materials and MethodsWe enrolled 100 patients including 13 healthy subjects, 12 non-AAs, 13 AAs, and 16 stage-I, 15 stage-II, 16 stage-III, and 15 stage-IV CRCs. These patients were classified as normal control, early neoplasia, and advanced neoplasia. The sEV proteome was explored by liquid chromatography-tandem mass spectrometry. Generalized association plots were used to integrate the clustering methods, visualize the data matrix, and analyze the relationship. The specific sEV biomarkers were identified by a decision tree via Orange3 software. Functional enrichment analysis was conducted by using the Ingenuity Pathway Analysis platform.ResultsThe sEV protein matrix was identified from the serum of 100 patients and contained 3353 proteins, of which 1921 proteins from 98 patients were finally analyzed. Compared with the normal control, subjects with early and advanced neoplasia exhibited a distinct proteomic distribution in the data matrix plot. Six sEV proteins were identified, namely, GCLM, KEL, APOF, CFB, PDE5A, and ATIC, which properly distinguished normal control, early neoplasia, and advanced neoplasia patients from each other. Functional enrichment analysis revealed that APOF+ and CFB+ sEV associated with clathrin-mediated endocytosis signaling and the complement system, which have critical implications for CRC carcinogenesis.ConclusionPatients with colorectal neoplasia had a distinct sEV proteome expression pattern in serum compared with those patients who were healthy and did not have neoplasms. Moreover, the six identified specific sEV proteins had the potential to discriminate colorectal neoplasia between early-stage and advanced neoplasia. Collectively, our study provided a six-sEV protein biomarker panel for CRC diagnosis at early or advanced stages. Furthermore, the implication of the sEV proteome in CRC carcinogenesis via specific signaling pathways was explored.

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Section: Discussionmentioning

confidence: 99%

Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia

et al. 2021

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“…23 Data from The Cancer Genome Atlas (TCGA) offered additional genetic evidence that 96.77% of patients with colon cancer did not have the PDE5 mutation and that patients without mutation of PDE5 suffered poorer survival rates compared with those with PDE5 mutation. 46 However, until now, there has been a lack of evidence based on population to support the anticancer effect of PDE5 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Use of Phosphodiesterase 5 Inhibitors Is Associated With Lower Risk of Colorectal Cancer in Men With Benign Colorectal Neoplasms

Huang

Sundquist

et al. 2019

Gastroenterology

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BACKGROUND & AIMS: Phosphodiesterase 5 (PDE5) inhibitors have been proposed to have chemopreventative effects on colorectal cancer (CRC), although data are needed from populationbased studies. We performed a nationwide cohort study to investigate the association between the use of PDE5 inhibitors and the risk of CRC in men with benign colorectal neoplasms. METHODS: We identified men who received a diagnosis of benign colorectal neoplasm from July 2005 through March 2015 who were listed in the Swedish Hospital Discharge Register. We linked data with those from other national Swedish registers to obtain information about the prescription of PDE5 inhibitors and CRC diagnoses. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: A total of 4823 patients were prescribed PDE5 inhibitors during the study period; the incidence rate of CRC was 2.64 per 1000 person-years for men prescribed PDE5 inhibitors compared with 4.46 per 1000 person-years for men without a prescription. We found a significant negative association between PDE5 inhibitor use and risk of CRC (adjusted HR, 0.65; 95% CI, 0.49-0.85); the decreased risk of CRC was associated with an increased cumulative dose of PDE5 inhibitors (P ¼ .003). PDE5 prescription was associated with greater reduction in risk of advanced-stage CRC (adjusted HR, 0.61; 95% CI, 0.37-1.00) than early-stage CRC (adjusted HR, 0.70; 95% CI, 0.50-0.98), but the difference was not significant. CONCLUSIONS: In a nationwide population-based study of men with a diagnosis of benign colorectal neoplasm in Sweden, we found evidence that use of PDE5 inhibitors is associated with a reduced risk of CRC. Further studies are needed to confirm the observed association.

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“…Few associations have been rigorously evaluated within randomized trials and, for those that have, the associations are often not sustained. 7 A reported increased risk of cardiovascular events in patients taking clopidogrel plus a proton pump inhibitor from observational data, for example, was not sustained by subsequent analyses of randomized trials, even though there was a plausible biological mechanism. 8,9 Indeed, trial data found that proton pump inhibitor use in this patient population decreased the risk of gastrointestinal events without a detectable increase in cardiovascular risk; thus, avoidance of proton pump inhibitors in this setting was actually associated with overall clinical harm.…”

Section: Conflicts Of Interestmentioning

confidence: 99%

“…Additional corroborating evidence includes the finding that patients with CRC in the Cancer Genome Atlas that harbor mutations associated with reduced PDE5 expression had longer survival. 7 Finally, experimental studies have shown that PDE5 inhibitors have anticancer activity in vitro 3,8 and in vivo in both inflammation-related 9-11 and inflammation-independent 12 cancer animal models.…”

mentioning

confidence: 99%

Are Phosphodiesterase-5 Inhibitors a New Frontier for Prevention of Colorectal Cancer?

Jovani

Chan

2019

Gastroenterology

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Mutations of the PDE5A Gene Confer a Survival Advantage in Patients with Colon Cancer

Cited by 7 publications

References 2 publications

Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia

Exploration of the Proteomic Landscape of Small Extracellular Vesicles in Serum as Biomarkers for Early Detection of Colorectal Neoplasia

Use of Phosphodiesterase 5 Inhibitors Is Associated With Lower Risk of Colorectal Cancer in Men With Benign Colorectal Neoplasms

Are Phosphodiesterase-5 Inhibitors a New Frontier for Prevention of Colorectal Cancer?

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