Epidemiological and biological data show a clear association between chronic inflammatory conditions and subsequent malignant transformation in the inflamed tissue . Inflammatory state is typically accompanied by generation of free radicals, stimulation of cytokines, chemokines, and growth and angiogenic factors that favor tumorigenesis by damaging DNA [2, 3], stimulating angiogenesis , and by inducing cell proliferation [5, 6]. Following these considerations, some pro-inflammatory genes have been shown to be important for the maintenance and progression of cancer , including colorectal cancer (CRC) [8, 9].
Toll-like and CD14 receptors are examples of pattern recognition receptors that detect antigenic molecules on the surface of gram-positive (peptidoglycans, lipoteichoic acid) and gram-negative (lipopolysaccharide, LPS) bacteria . Polymorphisms of TLR4 gene appear to be able to alter inflammatory responses in numerous experimental and clinical models of inflammation. Asp299Gly polymorphism [dbSNP: rs4986790] within TLR4 has been investigated by several groups and associated with an increased response to LPS . CD14 is a gene preferentially expressed on monocytes/macrophages generating a surface protein. It binds lipopolysaccharide-binding protein and recently has been shown to bind apoptotic cells . The polymorphism -260 T>C [dbSNP: rs2569190] has been shown to increase transcriptional activity by lowering the affinity of the GC box for Sp3, a factor known to inhibit the activity of a number of promoters. This enhanced transcriptional activity has been associated with higher concentrations of soluble CD14 and enhanced CD14 expression on the membrane of the monocytes .
MCP-1 is a chemokine that is thought to be responsible for monocyte and T-lymphocytes recruitment in acute inflammatory conditions and may be an important mediator in chronic inflammation. The G allele of -2518 A>G MCP1 polymorphism [dbSNP: rs1024611] was found to increase MCP-1 expression .
IL12A encodes a subunit (alpha) of a cytokine that is required for the T-cell-independent induction of interferon (IFN)-gamma. IL-12 was believed to be unique in its ability to induce the differentiation of native T cells toward the TH1 phenotype and in its pathogenic activity, as shown in various disease models including inflammatory bowel disease (IBD) . SNPs in the regulatory sequence of IL12A are presumed to be associated with the differential production of this cytokine .
Focusing on pathways involved more specifically in chronic inflammatory bowel disorders and CRC, the nitric oxide (NO) is a versatile molecule with actions ranging from haemodynamic regulation to anti-proliferative effects on vascular smooth muscle cells . NO is produced by the nitric oxide synthases, endothelial NOS (eNOS), neural NOS (nNOS), and inducible NOS (iNOS). NOS2A is the encoding gene for the inducible NOS. It is required for the signalling process in the innate immunity  and it plays a central role on chronic inflammatory bowel disorders .
Tumor necrosis factor (TNF; formerly known as TNFα) and lymphotoxin-α (LTA), originally characterized by their ability to induce tumor cell apoptosis and cachexia, are now considered as central mediators of a broad range of biological activities (for a review see  and ). These activities encompass beneficial effects for the host in inflammation and in protective immune responses against a variety of infectious pathogens . In addition, it has been demonstrated that the core members of the TNF superfamily, including LTα, play an essential role during the organogenesis of secondary lymphoid organs and the maintenance of the architecture of lymphatic tissues . Although a large study did not show association between polymorphisms within LTA-TNF region on chromosome 6 and IBD , the role of LTA in the etiology of IBD has been well ascertained in mice .
Several lines of evidence suggest that cyclo-oxygenases (COX) 1 and 2 enzymes, encoded by PTGS1 and PTGS2 genes, play a significant role in colon carcinogenesis. For example, rapid metabolism of arachidonic acid and elevated levels of COX enzymes are found in several cancers, including CRC . In addition, COX enzymes have been shown to stimulate cell proliferation, angiogenesis, and metastasis, and to inhibit apoptosis . During the inflammatory state COX enzymes are elevated, thus the regular use of non-steroidal anti-inflammatory drugs (NSAIDs) could be associated with a reduced risk of CRC, through their inhibition . While COX-2 is rapidly inducible and its expression is usually elevated at sites of inflammation, COX-1 is considered constitutive and is thought to be the main responsible for the cytoprotective production of prostaglandins. However, the traditional description of COX-1 as a purely constitutive, housekeeping gene has been recently challenged by several studies, which have found that COX-1 production can also be regulated at the transcriptional level .
In previous investigations, we performed a case-control association study on several polymorphisms in genes involved in the inflammation (namely: IL6, IL8, PPARG, TNF, NFKB1 and PTGS2) and we found associations with the risk of sporadic colorectal cancer [9, 28]. In the present study, in order to evaluate whether single nucleotide polymorphisms (SNPs) within more inflammatory genes were associated with the risk to develop CRC, we investigate ten SNPs in the following inflammatory genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 cases and 326 controls.