Traditional Risk Factors Are Not Associated with the Rise of Early-Onset Colorectal Cancer: An All of Us Study.

BACKGROUND: Colorectal cancer incidence is increasing among adults under age 50, yet the etiologic drivers remain unclear. The All of Us Research Program provides a unique opportunity to examine age-specific genetic and environmental associations with colorectal cancer risk in a diverse national cohort. OBJECTIVE: To determine whether a significant association exists between traditional environmental risk factors and established genetic variants and age-specific incidence patterns of early-onset colorectal cancer. DESIGN: Retrospective stratified case-control study using whole genome sequencing and electronic health records. Conditional logistic regression adjusted for genetic ancestry. SETTINGS: Diverse national cohort with integrated genomic data, electronic health records, and lifestyle surveys. PATIENTS: A total of 2,455 colorectal cancer patients (485 early-onset diagnosed before age 50, 1,970 late-onset diagnosed at age ≥50) matched 4:1 to 9,820 controls on birth year, sex, and race. MAIN OUTCOME MEASURES: Age-specific associations between environmental factors (family history, smoking timing, alcohol use disorders, body mass index) and 283 genetic variants with colorectal cancer risk. RESULTS: Family history was associated with higher odds uniformly across ages (odds ratio 2.10, 95% confidence interval 1.69-2.61). Heavy smoking during ages 20-40 was associated with late-onset but not early-onset disease (interaction p = 0.006). Alcohol use disorders and body mass index showed no age-specific effects. In genetic analyses, no variants demonstrated age-specific effects after correction for multiple comparisons (283 variants tested). No genetic pathways differed between early-onset and late-onset disease. Two variants were associated with rectal-specific risk (VTI1A rs4554812, FMN2 rs2078095). LIMITATIONS: Causal inference is limited by observational design. Self-reported exposures are subject to recall bias. Age-stratified analyses had limited power for rare genetic effects. CONCLUSIONS: Traditional environmental risk factors and established common genetic variants are not associated with the rising incidence of early-onset colorectal cancer. Thus, drivers of early-onset disease might include novel environmental exposures or early-life factors beyond traditional risk assessment. See Video Abstract.