Kathryn E. Royse

A prospective study of soluble receptor for advanced glycation end-products and colorectal cancer risk in postmenopausal women

OBJECTIVES Receptor for advanced glycation end products (RAGE) expressed on adipocytes and immune cells can bind to ligand N(ε)-(carboxymethyl)-lysine (CML) and trigger dysregulation of adipokines and chronic inflammation. Soluble RAGE (sRAGE) mitigates the detrimental effect of RAGE. We examined the associations between circulating levels of CML-AGE and sRAGE and colorectal cancer (CRC). METHODS In a case-cohort study of the Womens Health Initiative Study, blood levels of CML-AGE and sRAGE were measured using ELISA. We used multivariable Cox regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident CRC in relation to quartiles (Q) of biomarker levels. RESULTS Average follow-up was 7.8 years for 444 cases and 805 subcohort members. In the subcohort, CML-AGE and sRAGE were inversely correlated with BMI (P values<0.0001). Levels of CML-AGE and sRAGE were not associated with CRC. In BMI-specific analysis, the association between sRAGE and CRC was observed. Among women with BMI≥25kg/m(2), those with highest levels of sRAGE had significantly lower risk for CRC as compared to women with lowest levels of sRAGE (HRQ4versusQ1: 0.39; 95% CI: 0.17-0.91). This inverse association was not observed among women with BMI <25kg/m(2) (P value for interaction=0.01). CONCLUSIONS Among postmenopausal women, the RAGE pathway may be involved in obesity-related CRC.

Disparities in Kaposi sarcoma incidence and survival in the United States: 2000-2013

Objective Geographic and racial disparities may contribute to variation in the incidence and outcomes of HIV-associated cancers in the United States. Method Using the Surveillance, Epidemiology, and End Results (SEER) database, we analyzed Kaposi sarcoma (KS) incidence and survival by race and geographic region during the combined antiretroviral therapy era. Reported cases of KS in men from 2000 to 2013 were obtained from 17 SEER cancer registries. Overall and age-standardized KS incidence rates were calculated and stratified by race and geographic region. We evaluated incidence trends using joinpoint analyses and calculated adjusted hazard ratios (aHR) for overall and KS-specific mortality using multivariable Cox proportional hazards models. Results Of 4,455 KS cases identified in men younger than 55 years (median age 40 years), the annual percent change (APC) for KS incidence significantly decreased for white men between 2001 and 2013 (APC -4.52, p = 0.02). The APC for AA men demonstrated a non-significant decrease from 2000–2013 (APC -1.84, p = 0.09). Among AA men in the South, however, APC has significantly increased between 2000 and 2013 (+3.0, p = 0.03). In addition, compared with white men diagnosed with KS during the same time period, AA men were also more likely to die from all causes and KS cancer-specific causes (aHR 1.52, 95% CI 1.34–1.72, aHR 1.49, 95% CI 1.30–1.72 respectively). Conclusion Although overall KS incidence has decreased in the U.S., geographic and racial disparities in KS incidence and survival exist.

Abstract LB-160: Genetic variations in the AGEs/AGER pathway and risk of pancreatic cancer

Background: Chronic inflammation is implicated in pancreatic cancer carcinogenesis. Advanced glycation end-products (AGEs), which are rich in cooked red meat and cigarette smoke, can perpetuate inflammation by binding to the receptor for advanced glycation end products (AGER, also known as RAGE). We hypothesized that genetic variation of the AGEs/AGER pathway affects pancreatic cancer risk by modulating chronic inflammation. Methods: We conducted a two-stage case-control study to examine the association between 96 single nucleotide polymorphisms (SNPs) in 21 genes (GLO1, MSR1, PINK1, KIF17, AGPAT1, AKR1B1, DDOST, CD36, SCARB1, AGER, APP, HMGB1, S100A8, S100B, S100P, S100A12, MMP9, ADAM10, PPARG, NOTCH4, and PDGF) of the AGEs/AGER pathway and risk of pancreatic cancer. The discovery study was conducted in 672 pancreatic cancer cases and 1361 controls ascertained from the Women’s Health Initiative (WHI) Study matched on age, race/ethnicity and study arm. The validation study was conducted in a PANC4 pooled hospital-based case-control study of 1,034 women cases and 989 women controls. A pooled analysis of 1706 cases and 2350 controls was also performed. SNP data were obtained or imputed from the previously performed GWASs. Pancreatic cancer risk was calculated as odds ratios (ORs) and 95% confidence intervals (Cis) using logistic regression models adjusting for age, race/ethnicity, body mass index (BMI), type 2 diabetes, and smoking using an additive genetic model. The potential interaction between individual SNP and red meat intake and cigarette smoking was examined. A false discovery rate (FDR) adjusted q value Results: We identified 11 SNPs with raw P values Summary and Conclusion: We did not observe significant association between any of 96 single SNP and pancreatic cancer risk. However, we found combined set of SNPs in the GLO1, DDOST, and CD36 genes were associated with risk of pancreatic cancer. GLO SNP rs6932648 may modify the association between smoking and risk of pancreatic cancer. GLO1, DDOST, and CD36 are involved in detoxification or clearance of AGEs compounds. Further investigation of AGEs and receptors systems in pancreatic cancer is warranted. Citation Format: Guochong Jia, Kathryn Royse, Hongwei Tang, Donghui Li, Liang Chen, Lesley Tinker, Gloria Petersen, Alison Klein, Peter Richardson, Donna White, Haleh Sangi-Haghapeykar, Hashem B. El-Serag, Li Jiao. Genetic variations in the AGEs/AGER pathway and risk of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2017-LB-160

Abstract LB-382: A prospective study of soluble receptor for advanced glycation end products and adiponectin and pancreatic cancer in postmenopausal women

Obesity is a recognized pancreatic cancer risk factor. Obesity-associated chronic inflammation and insulin resistance as well as western diet are associated with increased circulating levels of advanced glycation end products (AGEs) levels. When AGEs bind to their receptor (RAGE) on adipocytes, an inflammatory cascade is triggered and dysregulation of adipokines can occur. Soluble RAGE (sRAGE) mitigates this negative effect by acting as a decoy receptor for AGEs. In a nested case-control study in the prospective Women9s Health Initiative study, we assessed the association between baseline levels of sRAGE and adiponectin and pancreatic cancer risk in post-menopausal women. Medical, lifestyle, diet data, anthropometric measurements and fasting blood were collected at baseline (1993-98). Serum sRAGE and adiponectin levels were immunoassay measured. With an average follow-up 14 years (thru 8/2013), we identified 494 incident cases with pancreatic cancer. Two controls were matched to each case by age, ethnicity, trial assignment and blood draw time (± 6 mos.). Multivariable conditional logistic regression analysis was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between sRAGE and adiponectin levels (quartile, Q) and pancreatic cancer after adjusting for waist-hip-ratio, diabetes, and dietary intake of alcohol, protein, saturated fat and carbohydrates. A total of 7.6% cases and 6.3% controls were current smokers. sRAGE was correlated with adiponectin among controls(r = 0.17, P Citation Format: Donna L. White, Ron Hoogeveen, Kathryn Royse, Liang Chen, Lesley Tinker, Tom Rohan, Eric Whitsel, Hashem B. El-Serag, Li Jiao. A prospective study of soluble receptor for advanced glycation end products and adiponectin and pancreatic cancer in postmenopausal women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-382.

Abstract 937: Soluble receptor for advanced glycation end-products is a player in obesity-related colorectal cancer

Insulin resistance, adiposity, and chronic inflammation contribute to colorectal cancer (CRC) development. N e -(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 Women9s 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 Q2 vs Q1 :0.53; 95% CI: 0.31-0.90; HR Q4 vs Q1 : 0.81; 95% CI: 0.46-1.42) (P trend = 0.95). This inverse association was evident among women who had BMI ≥ 25 kg/m 2 (HR Q2 vs Q1 : 0.49; 95% CI: 0.25-0.99; HR Q4 vs Q1 : 0.43, 95% CI: 0.19-0.97) (P trend = 0.22), but not among women with normal BMI (BMI Q4 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 (HR Q4 vs Q1 : 0.78, 95% CI: 0.48-1.37) (P trend = 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