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Systemic Lipid Peroxidation and Colorectal Cancer Risk: A Time-Varying Relationship
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DOI：10.1002/ijc.70585.png)
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Abstract
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Despite widespread interest, large randomized controlled trials have failed to demonstrate chemopreventive benefits of antioxidant supplementation, raising concerns about its efficacy and safety. Building on our prior observation of a time-dependent inverse association between systemic oxidative stress (OxS), assessed using nucleic acid oxidation biomarkers, and colorectal cancer (CRC) risk, we extended this investigation to systemic lipid peroxidation and evaluated whether a composite OxS index incorporating DNA, RNA, and lipid markers improves risk characterization. We conducted a nested case–control study within two Shanghai cohorts (1938 CRC cases) and replicated findings in a US cohort (285 cases). Systemic lipid peroxidation was assessed using urinary F2-isoprostanes (F2-IsoPs), quantified by UPLC-MS/MS. Conditional logistic regression estimated odds ratios (ORs) for CRC risk. Lower levels of 5-F2t-IsoP, a major F2-IsoP isomer generated exclusively via free radical oxidation, were associated with increased CRC risk in both the primary and replication cohorts. Time-dependent associations were evaluated in the Shanghai cohorts. For CRC diagnosed within 5 years following enrollment, multivariable-adjusted ORs (95% CI) at the 10th and 90th percentiles of 5-F2t-IsoP levels, relative to the median, were 1.57 (1.26–1.96) and 0.61 (0.42–0.89), respectively, indicating a 2.2-fold difference in risk. The composite OxS index showed an even stronger association (3.9-fold difference). No significant associations were observed for diagnoses beyond 5 years. This study provides new evidence that systemic OxS is inversely and time-dependently associated with CRC risk during later stages of disease development, raising concerns that lowering systemic OxS via high-dose antioxidant supplementation potentially carry unintended risks for high-risk individuals.
Keywords:
colorectal cancer risk
lipid peroxidation
nested case–control study
oxidative stress
time-varying association
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