Inflammatory Biomarkers, Genetics, and Survival among Colorectal Cancer Patients

Chronic inflammation significantly increases the risk of colorectal cancer (CRC) through inflammation-mediated mechanisms. Current evidence regarding the connection between circulating inflammatory biomarkers and CRC prognosis is limited to C-reactive protein (CRP) and interleukin (IL)-6. However, other inflammatory biomarkers with biologic relevance, such as monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin, are not well understood for their associations with CRC survival. Furthermore, the relevant timing of circulating inflammatory biomarker measurements remains unclear. Existing evidence is limited to pre-diagnostic or pre-operative measures. Circulating markers of inflammation measured after treatment, when CRC survivors are at greatest risk for disease recurrence and metachronous cancers, may be informative in predicting CRC outcomes. Most observational studies of circulating inflammatory biomarkers and CRC only had a one-time measurement of CRP which may not be representative of a person’s average exposure to chronic inflammation. Mendelian randomization utilizes inherited germline genetic markers known to be associated with CRP as non-modifiable markers of long-term susceptibility to chronic inflammation. It can minimize confounding and reverse causation that has hampered previous observational studies. In this dissertation, we aimed 1) to evaluate the association between post-treatment circulating concentrations of inflammatory biomarkers, including CRP, IL-6, MCP-1, adiponectin, and leptin, with overall and disease-specific mortality among stage II-III CRC patients, and 2) to determine the association of genetically explained levels of CRP and CRC survival using the Mendelian randomization approach. To achieve these aims, we first leveraged the existing data and biospecimens from the Seattle Colon Cancer Family Registry Cohort (SCCFR) and collected data on measures of all five circulating inflammatory biomarkers using stored plasma samples. Hazards ratios for circulating inflammation biomarkers were estimated from Cox proportional hazard regression models. Over the 10-year follow-up, we observed 94 out of 306 CRC patients (31%) died, and 53 (18%) had CRC as their primary cause of death. Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years after the blood draw, and CRC-specific mortality within the 1st year of blood draw. In contrast, post-treatment leptin was not associated with overall mortality but was inversely associated with CRC-specific mortality within the first year of blood draw. We observed dose-response effects of post-treatment circulating IL-6 and adiponectin on all-cause mortality over a 10-year follow-up period (p for trend<0.0001). Adiponectin was associated with higher CRC-specific mortality within the first year of blood draw whereas IL-6 remained significantly associated with a higher risk of CRC-specific mortality over 10 years although the effect sizes attenuated with time. CRP and MCP-1 were also associated with higher all-cause mortality over the 10-year follow-up as well as CRC-specific mortality within the first year of blood draw. However, no association was observed when restricting to patients with CRP<10 mg/L. We then used the genetic and phenotypic data from the International Survival Analysis in Colorectal Cancer Consortium (ISACC) to construct a genetic risk score for CRP based on 52 genetic variants identified from previous GWAS. We observed that genetically predicted CRP was not associated with CRC-specific survival (HD= -1.15, 95% CI: -2.76 to 0.47 per 100,000 person-year, P-value=0.16). No association was observed in subgroup analyses by stage at diagnosis and tumor location. Our findings support the role of post-treatment chronic inflammation in CRC progression and the potential of using inflammatory markers, particularly IL-6 and adiponectin, to identify subsets of patients at higher risk of overall and disease-specific mortality for targeted CRC surveillance and post-treatment care. Our observational findings of no associations between circulating CRP with CRC mortality when excluding those with CRP>10 mg/L are in line with the Mendelian randomization study results that genetically predicted circulating CRP concentration was not associated with CRC survival among individuals diagnosed with CRC. It suggests that lifetime exposure to chronic inflammation as measured by CRP is not associated with survival among CRC patients