Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.

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 microenviron...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Carina Pereira, Sara Queirós, Ana Galaghar, Hugo Sousa, Pedro Pimentel-Nunes, Catarina Brandão, Luís Moreira-Dias, Rui Medeiros, Mário Dinis-Ribeiro
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2014
Materias:
R
Q
Acceso en línea:https://doaj.org/article/dbe09f6887c3437aaa845c696b4f9a45
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:dbe09f6887c3437aaa845c696b4f9a45
record_format dspace
spelling oai:doaj.org-article:dbe09f6887c3437aaa845c696b4f9a452021-11-18T08:25:22ZGenetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.1932-620310.1371/journal.pone.0092000https://doaj.org/article/dbe09f6887c3437aaa845c696b4f9a452014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24694755/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Carina PereiraSara QueirósAna GalagharHugo SousaPedro Pimentel-NunesCatarina BrandãoLuís Moreira-DiasRui MedeirosMário Dinis-RibeiroPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e92000 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Carina Pereira
Sara Queirós
Ana Galaghar
Hugo Sousa
Pedro Pimentel-Nunes
Catarina Brandão
Luís Moreira-Dias
Rui Medeiros
Mário Dinis-Ribeiro
Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.
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.
format article
author Carina Pereira
Sara Queirós
Ana Galaghar
Hugo Sousa
Pedro Pimentel-Nunes
Catarina Brandão
Luís Moreira-Dias
Rui Medeiros
Mário Dinis-Ribeiro
author_facet Carina Pereira
Sara Queirós
Ana Galaghar
Hugo Sousa
Pedro Pimentel-Nunes
Catarina Brandão
Luís Moreira-Dias
Rui Medeiros
Mário Dinis-Ribeiro
author_sort Carina Pereira
title Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.
title_short Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.
title_full Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.
title_fullStr Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.
title_full_unstemmed Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.
title_sort genetic variability in key genes in prostaglandin e2 pathway (cox-2, hpgd, abcc4 and slco2a1) and their involvement in colorectal cancer development.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/dbe09f6887c3437aaa845c696b4f9a45
work_keys_str_mv AT carinapereira geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT saraqueiros geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT anagalaghar geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT hugosousa geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT pedropimentelnunes geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT catarinabrandao geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT luismoreiradias geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT ruimedeiros geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
AT mariodinisribeiro geneticvariabilityinkeygenesinprostaglandine2pathwaycox2hpgdabcc4andslco2a1andtheirinvolvementincolorectalcancerdevelopment
_version_ 1718421831387447296