Toll‐like receptor genes and their association with colon and rectal cancer development and prognosis

Abstract

Toll-like receptors (TLR) are mediators of inflammation in the gut and potentially important modulators of colon and rectal cancer risk. We use data from a population-based study of incident colon cancer cases (n=1,555) and controls (n=1,956) and rectal cancer cases (n=754) and controls (n=959). We evaluate genetic variation in TLR2 (6 SNPs), TLR3 (4 SNPs), and TLR4 (8 SNPs) with risk of developing colon or rectal cancer and survival after diagnosis. TLR3 rs11721827 was associated with rectal cancer (OR 1.27 95% CI 1.02,1.58 for AC/CC vs AA genotype Wald p 0.035; adjusted p 0.126); TLR3 rs3775292 and TLR4 rs11536898 were associated with colon cancer (OR 0.68 95% CI 0.49,0.95 for GG vs CC/CG and OR 0.50 95% CI 0.29,0.87 for AA vs. CA/CC respectively; Wald p=0.023 and 0.015; adjusted p=0.085 and 0.101 respectively). TLR2 rs7656411 and rs3804099 respectively interacted with NSAID use and cigarette smoking to alter risk of colon cancer (adjusted p=0.034 and 0.077); TLR3 rs11721827 interacted with NSAID use to alter risk of colon cancer (adjusted p=0.071). TLR3 rs3775292 interacted with dietary carbohydrates to alter colon cancer risk and with dietary carbohydrates and saturated fat to alter rectal cancer risk (adjusted p=0.064, 0.0035, and 0.025 respectively). Multiple SNPs in TLR2 and TLR4 were associated with colon cancer survival. Although few independent associations with TLR genes were observed, we observed significant interaction with TLR2 and TLR3 with hypothesized lifestyle factors. Interaction with dietary factors remained significant for rectal cancer after adjustment for multiple comparisons.

HIC1 Tumor Suppressor Loss Potentiates TLR2/NF-κB Signaling and Promotes Tissue Damage–Associated Tumorigenesis

“…34), we further investigated the relationship between Hic1 and Tlr2 expression. First, we generated a Tlr2-Luc reporter by subcloning genomic DNA harboring the Tlr2 promoter region before the luciferase sequence.…”

TLR2 Limits Development of Hepatocellular Carcinoma by Reducing IL18-Mediated Immunosuppression

“…The frequency of the Tlr2-196-174 del allele was significantly higher in patients with HCV-associated HCC. This phenomenon was noted not only in HCC but also in gastric cancer (28), colon cancer (29), and prostate cancer (30), further indicating the importance of TLR2 in tumor immunosurveillance.…”

Lack of Association of Three Common Polymorphisms in Toll-like receptors (TLRs), TLR2+597T>C, +1350C>T and Arg753Gln with Cancer Risk: a Meta-analysis

“…The reason was that ALL did not belong to solid tumors. Furthermore, for the +597T>C polymorphism (rs3804099), we updated two new studies (Kim et al, 2012;Slattery et al, 2012), and no significant association was found in Asians or Caucasians.…”

“…As shown in Figure 1, a total of 14 studies were finally identified (Nieters et al, 2006;Etokebe et al, 2009;Purdue et al, 2009;Ashton et al, 2010;Balistreri et al, 2010;Gast et al, 2011;Zeng et al, 2011;Junjie et al, 2012;Kim et al, 2012;Nischalke et al, 2012;Slattery et al, 2012;Yang et al, 2012;Pimentel-Nunes et al, 2013). For the +597T>C polymorphism (rs3804099), 8 studies were available, including a total of 3987 cases and 5079 controls.…”