Although the regular use of NSAIDs has been consistently effective in the primary prevention of colorectal tumors its use is currently compromised by the onset of serious gastrointestinal side effects in average-risk population. The rs689466A.G inCOX-2 gene had a synergetic effect in CRC oncogenesis that increased with allele dosage, further reinforcing its causative role in cancer development. The GG homozygous genotype enhanced the susceptibility for CRC onset by 2-fold and appeared to have a sex and smoking habits dependent behavior, with ever-smokers having a nearly 6-fold increased genetic predisposition for CRC. These data follow our previous observations from a preliminary study. Furthermore, two haplotypes containing either the XL-184 purchase rs689466G or the rs5275C alleles led to a 50% increase on the risk for CRC. The lack of consistency observed between epidemiological studies addressing the rs689466A.G SNP in different ethnic backgrounds or cancer models appears to suggest that not only population stratification and lifestyle habits might modulate this polymorphism behavior but also its influence might be cell, tissue and pathological condition-dependent. In fact, in a recently published study we reported that this polymorphism located at 21195 nucleotides upstream exon 1 increases COX-2 transcriptional activity in two colon cancer cell lines. This was also noticeable in human hepatoma cell lines but antagonizes the increased promoter activity observed for the rs689466 A allele in gastric cancer cell lines. COX-2 overexpression is suggested as one of the smoke-induced pathways involved in carcinogenesis. Tobacco contains more than 60 identified carcinogens and even though some, such as, nicotine and benzopyrene, were shown to trigger COX-2 expression through b-adrenoceptors and ERK1/2 pathways, respectively, the patho genesis of smoking related CRC is still understudied. Further functional studies are needed to elucidate the nature of this geneenvironment interaction. The rs5275T.C polymorphism, set at 8473 base pairs from exon 1 was previously associated with an increased risk for colorectal adenoma and here with a higher susceptibility for CRC in the context of the AGC haplotype. This T-to-C substitution in the 39UTR was proven to contribute to COX-2 overexpression by disrupting the miR-542-3p:mRNA interaction and thus decreasing COX-2 mRNA decay. As already mentioned, COX-2 has a predominant role in the synthesis of the pro-carcinogenic PGE2 bioactive lipid and the main molecular target of NSAIDs. In fact Chan and colleagues noticed that aspirin’s preventive role was exclusively effective in the subgroup of colon cancers overexpressing COX-2 enzyme. So, the genetic variability in COX-2 gene may help predict individuals 
at higher risk and expected to be exposed to higher levels of COX-2. Common diseases have proven to be much more challenging to understand, as they are ASP1517 HIF inhibitor thought to arise due to the synergetic effect of many different susceptibility DNA variants interacting with environmental factors. Although, we have noticed some interactions between the aforementioned tagSNPs and demographic/ lifestyle habits, the lack of complete characterization of the study population, decreased the statistical power and the scarcity of studies inquiring the influence of those environmental factors specifically in these key players in PGE2 pathway have compromise.