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

• Published in: PloS one 2014-04, Vol.9 (4)
• Main Authors: Pereira, Carina, Queiros, Sara, Galaghar, Ana, Sousa, Hugo, Pimentel-Nunes, Pedro, Brandao, Catarina, Moreira-Dias, Luis, Medeiros, Rui, Dinis-Ribeiro, Mario
• Format: Article
• Language: English
• Subjects: Analysis; Care and treatment; Colorectal cancer; Development and progression; Diagnosis; Genetic polymorphisms; Prostaglandins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092000

The pro-carcinogenic effects of prostaglandin [E.sub.2] (PG[E.sub.2]) 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 PG[E.sub.2] 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 massspectrometric 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 PG[E.sub.2] 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.