Abstract 4132: Expression of pattern recognition receptor genes and survival in colorectal adenocarcinoma
Authors: Chen Liang , Berger David , Ittmann Michael , El-Serag Hashem B. , Balentine Courtney J. , Graham David Y. , Richardson Peter A. , Spitz Margaret R. , Hilsenbeck Susan G. , Rumbaut Rolando , Duan Zhigang , White Donna L. , Jiao Li 
Published: May 2015

Abstract
Chronic inflammation is one of the hallmarks of colorectal cancer. Pattern recognition receptors (PRRs) recognize dietary nutrients, bacterial components, and damage signals, and hence play an important role in innate immunity and chronic inflammation. Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) are PRRs that trigger NF-kB activation by binding to ligands, such as high mobility group 1 (HMGB1) and S100 protein family. However, the potential role of PRRs in colorectal cancer prognosis is unclear. We investigated the association between epithelial gene expression of TLRs, RAGE, their ligands, and inflammatory effectors and survival of patients with colorectal adenocarcinoma (CRAC). From a clinical surgical registry (2002-2012) at the Michael E. DeBakey VA Medical Center in Houston, we randomly selected 32 male patients and obtained their formalin-fixed, paraffin-embedded specimens of primary CRAC and paired adjacent normal mucosa. The mucosal epithelia were macrodissected. Multiplex quantitative nuclease protection assay was used to simultaneously quantify the expression levels for TLRs 2, 3, 4, and 5, RAGE, HMGB1, S100P, MyD88, IL-1β, and IL-8. Levels of expression were calculated as average pixel intensity for the spot image on the array plate and normalized to RPL6 and RPS13. Demographic and clinical information was abstracted from the electronic medical records. Wilcoxon test was used to compare expression levels of each gene between the tumor and the paired normal adjacent epithelia. Log-rank test was used to compare the survival function between those with high versus low expression of genes (using the median as the cutoff) in the tumor epithelia, and multivariate Cox regression model was used to estimate hazard ratio of dying. Survival time was calculated from the date of diagnosis to death or May 31, 2013. Of 32 patients with mean age 64, 18 had stage 0-IIA tumor and 24 did not receive neoadjuvant therapy. During a mean follow-up of 54 months, 15 (46.9%) patients died and 13 died within 36 months after diagnosis. Expression levels of TLR3, TLR5, MyD88, and RAGE were significantly lower, and TLR4 and IL-8 were significantly higher in the tumor epithelia compared with the paired normal mucosa (P &lt; 0.05). Three-year survival rate was 82% versus 42% for those with higher versus lower expression of TLR5 (P = 0.01); and 76% versus 47% for those with higher versus lower expression of RAGE (P =0.05), in tumor epithelia respectively. Cox regression analysis adjusting for age and stage showed that higher expression levels of TLR5 in tumor epithelia were associated with reduced hazard of dying (HR = 0.23, 95% CI: 0.07-0.80). This inverse association was observed for both early and late stage of CRAC. We did not observe any consistent or significant association for other genes. Our study supports the notion that TLR5, a PRR that detects bacterial flagellins, may play a role in anti-tumor response in CRAC.
Citation Format: Liang Chen, David Berger, Michael Ittmann, Hashem B. El-Serag, Courtney J. Balentine, David Y. Graham, Peter A. Richardson, Margaret R. Spitz, Susan G. Hilsenbeck, Rolando Rumbaut, Zhigang Duan, Donna L. White, Li Jiao. Expression of pattern recognition receptor genes and survival in colorectal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4132. doi:10.1158/1538-7445.AM2014-4132