C-reactive Protein and Future Risk of Clinical and Molecular Subtypes of Colorectal Cancer

Abstract

Background:Inflammation has been implicated in colorectal cancer (CRC) etiology, but the relationship between C-reactive protein (CRP) and CRC risk is unclear. We aimed to investigate the association between pre-diagnostic plasma CRP concentrations and the risk of clinical and molecular CRC subtypes. Methods:We used prospectively collected samples from 1010 matched CRC case-control pairs from two population-based cohorts in Northern Sweden, including 259 with repeated samples. Conditional logistic regression and linear mixed models were used to estimate relative risks of CRC, including subtypes based on BRAF and KRAS mutations, microsatellite instability status, tumor location, stage, lag-time, and (using unconditional logistic regression) BMI. Results:CRP was not associated with CRC risk, regardless of clinical or molecular CRC subtype. For participants with advanced tumors and blood samples <5 years before diagnosis, CRP was associated with higher risk (odds ratio per 1 unit increase in natural logarithm-transformed (ln) CRP 1.32, 95% CI 1.01-1.73). CRP levels increased over time, but average time trajectories were similar for cases and controls (Pinteraction=0.19). Conclusions:Our results do not support intertumoral heterogeneity as an explanation for previous inconsistent findings regarding the role of CRP in CRC etiology. The possible association in the subgroup with advanced tumors and shorter follow-up likely reflects undiagnosed cancer at baseline. Impact:Future efforts to establish the putative role of chronic, low-grade inflammation in CRC development will need to address the complex relationship between systemic inflammatory factors and tumor microenvironment, and might consider larger biomarker panels than CRP alone.