Evaluating Risk Factors for Early-Onset Colorectal Cancer in a Large, Prospective Cohort

Background Despite the worrisome rise of early-onset colorectal cancer (EOCRC), risk factors have not been definitively established. We use a large, granular database to evaluate risk factors for EOCRC, investigate differences in associations with EOCRC and later-onset CRC (LOCRC), and compare metrics of accelerated aging, a hypothesized driver of EOCRC. Methods This was a case-control analysis within the UK Biobank. Risk factors for each cancer were identified and compared, including aging measures (chronological age, telomere length, PhenoAge, and homeostatic dysregulation). Results A total of 31,164 persons were matched. We found an increased risk of EOCRC with PRS (OR 1.53; 95% CI 1.19-1.97; p < 0.001). LOCRC was associated with increasing PRS (OR 1.48; 95% CI 1.44 - 1.53; p < 0.001), increasing waist-to-hip ratio (OR 5.81; 95% CI 3.25 - 10.38; p < 0.001), family history of CRC (OR 1.27; 95% CI 1.16 - 1.40; p < 0.001), and history of smoking (OR 1.11; 95% CI 1.03 - 1.19; p = 0.01). Male sex and prior CRC screening were associated with reduced risk of LOCRC. The inclusion of PhenoAge as the measure of aging demonstrated the best model fit for both EOCRC and LOCRC. For each year that PhenoAge exceeded chronological age, the odds of EOCRC increased by 7%, while odds of LOCRC only increased by 1%. Conclusions Within this study, we find that genetic risk variants are a significant driver of EOCRC risk. Accelerated aging appears to be associated with increased risk of both EOCRC and LOCRC, and measures such as PhenoAge warrant continued study.