Laboratory experiments suggest that activation of receptor for advanced glycation end products (RAGE) contributes to liver injury and blockade of RAGE with soluble RAGE (sRAGE) may mitigate the effects of RAGE activation. Epidemiologic studies examining sRAGE and advanced glycation end products (AGEs) in relation to liver cancer are sparse. Within a cohort of 29,133 Finnish male smokers who completed questionnaires and donated blood samples between 1985-1988, we conducted a case-cohort study examining the associations between serum concentrations of sRAGE or Nϵ-(carboxymethyl)-lysine (CML)-AGE, the most abundant AGE in humans, in association with liver cancer. During follow-up that began 5 years after enrollment through April 2006, 145 liver cancer cases occurred. Serum levels of sRAGE, CML-AGE, glucose and insulin were measured in cases and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were also measured. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). Multivariate models were adjusted for age, years of smoking, and body mass index. Among subcohort participants, carbohydrate and sucrose intake increased across increasing tertiles of serum sRAGE (P-values ≤0.01). After adjusting for age, BMI and years of smoking, serum sRAGE concentration was inversely associated with liver cancer risk [continuous RR (95% CI): 0.86 (0.75-0.99), P-value=0.04]. Unexpectedly, serum CML concentration was also inversely associated with liver cancer risk [continuous RR (95% CI): 0.74(0.65-0.84), P-value <0.0001]. Further adjustment for serum glucose and insulin did not change the associations. The prevalence of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (anti-HBc) titers measured on 135 cases were 0.75% and 13%, respectively and 3% for hepatitis C exposure (anti-HCV). Exclusion of cases with chronic HBV or HCV did not change our results. Our results support the hypothesis that sRAGE is inversely associated with liver cancer. The findings need confirmation, particularly in populations that include women and non-smokers.

Citation Format: Kristin A. Moy, Li Jiao, Neal D. Freedman, Stephanie J. Weinstein, Rashmi Sinha, Jarmo Virtamo, Demetrius Albanes, Rachael Stolzenberg-Solomon. Soluble RAGE modestly inversely associated with liver cancer risk in male Finnish smokers. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 19.