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...
Guardado en:
Autores principales: | , , , , , , , , |
---|---|
Formato: | article |
Lenguaje: | EN |
Publicado: |
Public Library of Science (PLoS)
2014
|
Materias: | |
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 |