Abstract
Colorectal cancer prognosis is dependent on stage, and measures to improve early detection are urgently needed. Using prospectively collected plasma samples from the population-based Northern Sweden Health and Disease Study, we evaluated protein biomarkers in relation to colorectal cancer risk. Applying a two-tiered approach, we analyzed 160 proteins in matched sequential samples from 58 incident colorectal cancer case–control pairs. Twenty-one proteins selected from both this discovery phase and the literature were then analyzed in a validation set of 450 case–control pairs. Odds ratios were estimated by conditional logistic regression. LASSO regression and ROC analysis were used for multi-marker analyses. In the main validation analysis, no proteins retained statistical significance. However, exploratory subgroup analyses showed associations between FGF-21 and colon cancer risk (multivariable OR per 1 SD: 1.23 95% CI 1.03–1.47) as well as between PPY and rectal cancer risk (multivariable OR per 1 SD: 1.47 95% CI 1.12–1.92). Adding protein markers to basic risk predictive models increased performance modestly. Our results highlight the challenge of developing biomarkers that are effective in the asymptomatic, prediagnostic window of opportunity for early detection of colorectal cancer. Distinguishing between cancer subtypes may improve prediction accuracy. However, single biomarkers or small panels may not be sufficient for effective precision screening.
Highlights
Colorectal cancer prognosis is dependent on stage, and measures to improve early detection are urgently needed
Neither smoking nor alcohol intake varied between cases and controls in either of the datasets
Due to the study design, the mean age at colorectal cancer diagnosis was lower in the discovery set (60.6 years compared to 66.6 years in the validation set) (Table 1)
Summary
Colorectal cancer prognosis is dependent on stage, and measures to improve early detection are urgently needed. Efforts to supplement colorectal cancer screening programs with blood tests for sub-clinical disease presence are ongoing[4,5], including the FDA-approved test for Septin 9 DNA methylation[6] Such tests use diagnostic biomarkers, i.e. biomarkers of disease, as an acceptable, minimally invasive and resource-effective means of selecting screening participants for colonoscopy. Another approach to refining general screening programs is through population-based risk stratification, in the hope of identifying higher-risk groups for earlier and/or more frequent screening. A recent case-cohort study based in Japan, using a panel of 62 inflammatory biomarkers, identified a number of chemokines putatively related to subsequent colorectal cancer risk[12] These have not been replicated in an independent sample
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