Researchers followed 405,453 cancer-free UK Biobank participants aged 38-73 for a median 13.65 years, recording 6,620 colorectal cancers. Polygenic risk and an eight-factor lifestyle score were analysed by onset age: under 55, 55-64, 65-74, 75 or older. High versus low genetic risk gave hazard ratios of 3.72, 3.32, 2.80 and 2.01 respectively. For unfavourable versus favourable lifestyle, hazard ratios were 1.10, 1.50, 1.58 and 1.28. Relative excess risk due to interaction was 0.37 (intermediate) and 1.01 (high genetic risk) from 55, but not detected before. Early-onset cases numbered only 387, participants were mostly white, and lifestyle was measured once.
Why it is interesting: Hazard ratios for polygenic risk were highest for colorectal cancer diagnosed before 55, where lifestyle showed little association. Excess risk from combining genetic risk with an unfavourable lifestyle appeared only in cancers diagnosed from age 55.
Abstract — the authors' own words, CC BY
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 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.
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