Time-dependent relationship between urinary biomarkers of nucleic acid oxidation and colorectal cancer risk.

Purpose: Randomized controlled trials have failed to validate that neutralizing oxidative stress (OxS) through antioxidant supplementation reduces cancer risk. This study aims to prospectively investigate whether the relationship between systemic OxS and colorectal cancer (CRC) risk changes over the course of cancer development.

Methods: This study utilized a nested case-control design in two Shanghai cohorts for primary analysis and one US cohort for replication analysis. During a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident CRC cases were identified and matched to one control each. In the US cohort, 285 incident CRC cases were included with two matched controls per case. Systemic OxS was assessed by urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) using UPLC-MS/MS assays. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated.

Results: After adjusting for potential confounders, we observed an inversion association between OxS markers and CRC risk in the Shanghai cohorts, which was independently replicated in the US cohort. Moreover, the inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years of enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating an approximate 4-fold difference in risk between the two groups, with for overall association of < 0.001. A similar pattern was observed for 8-oxo-Guo. No significant association was found for CRC diagnosed beyond 5 years of enrollment.

Conclusion: This novel finding of an inverse and time-dependent relationship between systemic OxS and CRC risk, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.

Context: Almost all large randomized controlled trials have failed to validate the hypothesis that neutralizing oxidative stress through antioxidant supplementation can lower cancer risk, which has puzzled the public and researchers for decades. A reduced risk for colorectal cancer (CRC) with increasing systemic oxidative stress, measured by two urinary biomarkers of DNA and RNA oxidation, was observed in two large prospective cohort studies in Shanghai, China, and was replicated in an independent cohort in the United States. This association was time-dependent, with the inverse relationship strengthening as the biomarker assessment neared the time of CRC diagnosis. Our study, for the first time, suggests an inverse and time-dependent relationship between systemic oxidative stress and CRC development, which, if further confirmed, may provide a new perspective for revisiting redox-based chemoprevention.