Insulin resistance, adiposity, and chronic inflammation contribute to colorectal cancer (CRC) development. Nϵ-(carboxymethyl)-lysine (CML) is a well-characterized type of advanced glycation end product (AGE). It can bind to the receptor for AGEs (RAGE) and trigger insulin resistance and sustained chronic inflammation. Soluble RAGE (sRAGE) mitigates the detrimental effect of RAGE by acting as a decoy receptor for its ligands. In a case-cohort study within the Women's Health Initiative Observational study, we examined the association between CML-AGE, sRAGE and risk of CRC among 447 cases and 802 subcohort controls. Information on lifestyle, anthropometry, medical history, and diet were collected at baseline. Levels of CML-AGE and sRAGE were measured by ELISA using fasting blood collected at baseline. Circulating levels of adipokines, insulin, glucose, estradiol, and C-reactive protein were previously measured for the study subjects. Multivariate Cox proportional hazard regression model accounting for the case-cohort design was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for CRC according to quartile (Q) of biomarkers with adjustment for age, race, waist circumstance, smoking, family history of colorectal cancer, NASID, energy intake, physical activity, alcohol consumption, saturated fat intake, available carbohydrate intake, hypertension, hormone replacement therapy, calcium, folate equivalent, red meat, insulin, and adiponectin. Average participant follow-up was 7.8 years. Among 802 subcohort controls, CML-AGE and sRAGE were both significantly inversely correlated with BMI, waist circumference, serum insulin, glucose, and leptin, but positively correlated with adiponectin (P values < 0.05). sRAGE levels were inversely associated with CRC (HRQ2 vs Q1:0.53; 95% CI: 0.31-0.90; HRQ4 vs Q1: 0.81; 95% CI: 0.46-1.42) (Ptrend = 0.95). This inverse association was evident among women who had BMI ≥ 25 kg/m2 (HRQ2 vs Q1: 0.49; 95% CI: 0.25-0.99; HRQ4 vs Q1: 0.43, 95% CI: 0.19-0.97) (Ptrend = 0.22), but not among women with normal BMI (BMI < 25) (HRQ4 vs Q1: 1.72, 95% CI:0.53-5.55) (P value for interaction was 0.01). CML-AGE was not associated with CRC risk (HRQ4 vs Q1: 0.78, 95% CI: 0.48-1.37) (Ptrend = 0.18). We found pre-diagnostic sRAGE levels were inversely associated with risk of CRC among overweight and obese postmenopausal women. This study identifed the RAGE pathway as a potential etiological factor in obesity-associated CRC.

Citation Format: Liang Chen, Zhigang Duan, Lesley Tinker, Haleh Sangi-Haghpeykar, Howard Strickler, Gloria Ho, Thomas Rohan, Marc Gunter, Craig Logsdon, Donna White, Kathryn Royse, Hashem El-Serag, Li Jiao. Soluble receptor for advanced glycation end-products is a player in obesity-related colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 937. doi:10.1158/1538-7445.AM2015-937