EP213 - Distinction Risk Factor Profiles for Early-Onset Colorectal Cancer: An All of Us Study

Purpose/Background: Colorectal cancer (CRC) incidence is increasing among adults under age 50, yet the etiologic drivers remain unclear. While rare pathogenic variants explain familial clustering, whether common genetic susceptibility contributes more strongly to early-onset disease in the general population, or whether traditional modifiable risk factors play comparable roles across age groups, is unknown. The National Institutes of Health All of Us Research Program, a diverse national cohort linking whole genome sequencing with electronic health records and environmental exposures, provides a unique opportunity to examine age-specific and location-specific genetic and environmental associations with CRC risk.

Methods/Interventions: CRC patients were classified by tumor location (left colon, right colon, or rectum). Three analyses were performed: (1) genetic associations using 185 CRC-associated population variants adjusted for ancestry and grouped into 9 pathways (Wnt/BMP/TGF-beta signaling, DNA repair, cell adhesion, chromatin regulation, immune response, metabolism, transcription, G-protein signaling, growth factors); (2) environmental associations (including smoking intensity and timing, alcohol use disorders, and obesity) with controls (4:1 ratio) matched on birth year (±2 years), sex, and race; and (3) stratified comparisons by age at diagnosis (early-onset < 50 vs late-onset ≥50) and separately by tumor location. Age-specific effects were tested using stratified case-control analysis, comparing early-onset and late-onset patients to their respective matched controls, with adjustment for sex and race within each age stratum.

Results/Outcomes: Among 2,482 CRC patients (491 early-onset, 1,991 late-onset), 2,048 had whole genome sequencing (33% non-European ancestry). Family history was associated with CRC (OR=2.34, 95% CI: 1.30-4.19, p=0.004) but did not differ by age at diagnosis. Environmental factors showed variable associations: smoking (OR=1.05, p=0.32), alcohol disorders (OR=1.68, p< 0.001), obesity (OR=1.05, p=0.61). Heavy smoking (≥1 pack/day, ages 20-40) was associated with late-onset CRC (OR=1.25, 95% CI: 1.09-1.45, p=0.002) but not early-onset CRC (OR=0.64, 95% CI: 0.41-1.01, p=0.055; p-interaction=0.006). Alcohol use disorder was associated with both early-onset (OR=1.31, 95% CI: 0.76-2.28, p=0.33) and late-onset CRC (OR=1.70, 95% CI: 1.35-2.13, p< 0.001; p-interaction=0.40). Among 283 variants tested, 10 showed nominal age-specific effects (p < 0.05) but no variants remained significant after multiple testing correction (FDR q>0.05). No pathways showed age-specific effects. Two variants were associated with rectal tumors (rs4554812 in VTI1A, OR=1.46, q=0.035; rs2078095 in FMN2, OR=1.30, q=0.040).

Conclusion/Discussion: Traditional genetic and environmental risk factors do not explain the rising incidence of early-onset colorectal cancer. CRC-associated genetic variants showed no age-specific effects. Heavy smoking during ages 20-40 was associated with late-onset but not early-onset CRC, consistent with decades-long carcinogenic latency, while alcohol use disorder increased risk uniformly across ages. Two gene variants (VTI1A, FMN2) were associated with rectal tumor location. These findings suggest early-onset and late-onset CRC arise through distinct pathways, and that early-onset risk factors remain unidentified and may involve novel environmental exposures, early-life factors, or gene-environment interactions.

Early-Onset Colorectal Cancer: Age and Location