Genetic Risk, Lifestyle, and Colorectal Cancer Across Age at Onset: A Prospective UK Biobank Study

BACKGROUND: Polygenic risk scores (PRS) and lifestyle factors are associated with colorectal cancer (CRC), but whether their associations and joint effects vary according to age at CRC onset remains unclear. We evaluated age-related heterogeneity in the associations of genetic risk and lifestyle with CRC and examined their additive interaction in early- and late-onset CRC. METHODS: We analyzed data from 405,453 cancer-free participants aged 38-73 years at baseline in the UK Biobank. PRS and a healthy lifestyle score (based on eight modifiable factors) were assessed. Age-scale Cox proportional hazards models estimated hazard ratios (HRs) for CRC risk by age at onset. Heterogeneity across age intervals was assessed using likelihood ratio tests. Additive interaction was assessed using the relative excess risk due to interaction (RERI), and differences in standardized incidence rates were evaluated. RESULTS: During a median follow-up of 13.65 years, 6620 CRC cases were identified. Compared with low genetic risk, high genetic risk was associated with HRs of 3.72, 3.32, 2.80, and 2.01 for CRC occurring at ages < 55, 55-64, 65-74, and ≥ 75 years, respectively, with significant heterogeneity across age intervals (p for heterogeneity < 0.001). Compared with a favorable lifestyle, the corresponding HRs for an unfavorable lifestyle were 1.10, 1.50, 1.58, and 1.28, respectively, with evidence of overall heterogeneity (p for heterogeneity = 0.015). For late-onset CRC, positive additive interactions were observed for an unfavorable lifestyle combined with intermediate or high genetic risk, whereas no such interaction was detected for early-onset CRC. CONCLUSIONS: The associations of genetic susceptibility and baseline lifestyle with CRC varied according to age at onset. Positive additive interaction between genetic risk and an unfavorable lifestyle was observed for late-onset but not early-onset CRC. These findings provide further evidence that the relative and joint associations of genetic and lifestyle factors with CRC vary across the life course.