Dataset Information

Influence of Genetic Polymorphisms in Prostaglandin E2 Pathway (COX-2/HPGD/SLCO2A1/ABCC4) on the Risk for Colorectal Adenoma Development and Recurrence after Polypectomy.

ABSTRACT: Deregulation of prostaglandin E2 (PGE2) levels reported in colorectal carcinogenesis contributes to key steps of cancer development. Our aim was to evaluate the influence of the genetic variability in COX-2/HPGD/SLCO2A1/ABCC4 PGE2 pathway genes on the development and recurrence of colorectal adenomas.A case-control study was conducted gathering 480 unscreened individuals and 195 patients with personal history of adenomas. A total of 43 tagSNPs were characterized using the Sequenom platform or real-time PCR.Ten tagSNPs were identified as susceptibility biomarkers for the development of adenomas. The top three most meaningful tagSNPs include the rs689466 in COX-2 (odds ratio (OR)=3.23; 95% confidence interval (CI): 1.52-6.86), rs6439448 in SLCO2A1 (OR=0.38; 95% CI: 0.22-0.65) and rs1751051 in ABCC4 genes (OR=2.75; 95% CI: 1.58-4.80). The best four-locus gene-gene interaction model included the rs1346271, rs1863642 and rs12500316 single nucleotide polymorphisms in HPGD and rs1678405 in ABCC4 genes and was associated with a 13-fold increased susceptibility (95% CI: 3.84-46.3, P<0.0001, cross-validation (CV) accuracy: 0.78 and CV consistency: 8/10). Interesting, in low-risk patients the ABCC4 rs9524821AA genotype was associated not only with a higher hazard ratio (HR=2.93; 95% CI: 1.07-8.03), but half of these patients had adenoma recurrence at 60 months, considerably higher than the 21% noticed in low-risk patients.Genetic polymorphisms in COX-2/PGE2 pathway appear to contribute to the development of colorectal adenomas and influence the interval time to adenomas recurrence. The definition of risk models through the inclusion of genetic biomarkers might improve the adherence and optimization of current screening and surveillance guidelines for colorectal cancer prevention.

SUBMITTER: Pereira C

PROVIDER: S-EPMC5288593 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Influence of Genetic Polymorphisms in Prostaglandin E2 Pathway (COX-2/HPGD/SLCO2A1/ABCC4) on the Risk for Colorectal Adenoma Development and Recurrence after Polypectomy.

Pereira Carina C Queirós Sara S Galaghar Ana A Sousa Hugo H Marcos-Pinto Ricardo R Pimentel-Nunes Pedro P Brandão Catarina C Medeiros Rui R Dinis-Ribeiro Mário M

Clinical and translational gastroenterology 20160915 9

<h4>Objectives</h4>Deregulation of prostaglandin E2 (PGE2) levels reported in colorectal carcinogenesis contributes to key steps of cancer development. Our aim was to evaluate the influence of the genetic variability in COX-2/HPGD/SLCO2A1/ABCC4 PGE2 pathway genes on the development and recurrence of colorectal adenomas.<h4>Methods</h4>A case-control study was conducted gathering 480 unscreened individuals and 195 patients with personal history of adenomas. A total of 43 tagSNPs were characterize ...[more]

PMID: 27628421

Similar Datasets

Project description:The pro-carcinogenic effects of prostaglandin E2 (PGE2) in colonic mucosa are not only regulated by the rates between Cyclooxygenase-2 (COX-2) biosynthesis and 15-Hydroxyprostaglandin Dehydrogenase (15-PGDH)-dependent degradation but also the steady-state levels of PGE2 in extracellular microenvironment, maintained by key specific prostaglandin transporters, the Multidrug Resistance Protein (MRP4) (efflux carrier) and Prostaglandin Transporter (PGT) (influx carrier). To understand the contribution of genetic variability in genes coding for COX-2/15-PGDH/MRP4/PGT proteins in CRC development, we conducted a hospital-based case-control study involving 246 CRC patients and 480 cancer-free controls. A total of 51 tagSNPs were characterized using the Sequenom platform through multiplexed amplification followed by mass-spectrometric product separation or allelic discrimination using real-time PCR. Seven tagSNPs were implicated in CRC development: the rs689466 in COX-2 gene, the rs1346271 and rs1426945 in 15-PGDH, the rs6439448 and rs7616492 in PGT and rs1751051 and rs1751031 in MRP4 coding genes. Upon a stratified analysis a measurable gene-environment interaction was noticed between rs689466 and smoking habits, with individuals ever-smokers carriers of rs689466 GG homozygous genotype having a nearly 6-fold increased susceptibility for CRC onset (95%CI: 1.49-22.42, P = 0.011). Furthermore, the multifactor dimensionality reduction (MDR) analysis identified an overall four-factor best gene-gene interactive model, including the rs1426945, rs6439448, rs1751051 and rs1751031 polymorphisms. This model had the highest cross-validation consistency (10/10, P<0.0001) and an accuracy of 0.6957 and was further associated with a 5-fold increased risk for CRC development (95%CI: 3.89-7.02, P<0.0001). In conclusion, specific low penetrance genes in the pro-carcinogenic PGE2 pathway appear to modulate the genetic susceptibility for CRC development. A clearer understanding on CRC etiology through the identification of biomarkers of colorectal carcinogenesis might allow a better definition of risk models that are more likely to benefit from targeted preventive strategies to reduce CRC burden.

Project description:Vasodilatory prostaglandins play a key role in neurovascular coupling (NVC), the tight link between neuronal activity and local cerebral blood flow, but their precise identity, cellular origin and the receptors involved remain unclear. Here we show in rats that NMDA-induced vasodilation and hemodynamic responses evoked by whisker stimulation involve cyclooxygenase-2 (COX-2) activity and activation of the prostaglandin E2 (PgE2) receptors EP2 and EP4. Using liquid chromatography-electrospray ionization-tandem mass spectrometry, we demonstrate that PgE2 is released by NMDA in cortical slices. The characterization of PgE2 producing cells by immunohistochemistry and single-cell reverse transcriptase-PCR revealed that pyramidal cells and not astrocytes are the main cell type equipped for PgE2 synthesis, one third expressing COX-2 systematically associated with a PgE2 synthase. Consistent with their central role in NVC, in vivo optogenetic stimulation of pyramidal cells evoked COX-2-dependent hyperemic responses in mice. These observations identify PgE2 as the main prostaglandin mediating sensory-evoked NVC, pyramidal cells as their principal source and vasodilatory EP2 and EP4 receptors as their targets.Significance statementBrain function critically depends on a permanent spatiotemporal match between neuronal activity and blood supply, known as NVC. In the cerebral cortex, prostaglandins are major contributors to NVC. However, their biochemical identity remains elusive and their cellular origins are still under debate. Although astrocytes can induce vasodilations through the release of prostaglandins, the recruitment of this pathway during sensory stimulation is questioned. Using multidisciplinary approaches from single-cell reverse transcriptase-PCR, mass spectrometry, to ex vivo and in vivo pharmacology and optogenetics, we provide compelling evidence identifying PgE2 as the main prostaglandin in NVC, pyramidal neurons as their main cellular source and the vasodilatory EP2 and EP4 receptors as their main targets. These original findings will certainly change the current view of NVC.

Dataset Information

Influence of Genetic Polymorphisms in Prostaglandin E2 Pathway (COX-2/HPGD/SLCO2A1/ABCC4) on the Risk for Colorectal Adenoma Development and Recurrence after Polypectomy.

Publications

Influence of Genetic Polymorphisms in Prostaglandin E2 Pathway (COX-2/HPGD/SLCO2A1/ABCC4) on the Risk for Colorectal Adenoma Development and Recurrence after Polypectomy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure