10500 Background: Early-onset cancer (EoC, defined as any solid tumor diagnosed ≤50 years age) incidence has increased 79% globally since 1990. Traditional risk models focus on isolated exposures or specific rare genetic variants and have limited utility for EoC, as high-penetrance mutations account for <10-20% of cases depending on tumor type. Allostatic load (AL) – the cumulative physiological burden of chronic stress across neuroendocrine, immune, and metabolic systems – may represent a pan-EoC mechanism linking environmental exposures to EoC carcinogenesis. Methods: We analyzed 13,745 adults aged ≤50 years (2,749 EoC cases) across two population-based cohorts: UK Biobank (UKB; n=5,100) and NIH All of Us Research Program (AoU; n=8,645). AL was constructed by summing standardized indicators for 8-11 baseline biomarkers representing cardiovascular (blood pressure), metabolic (HbA1c, glucose, cholesterol, BMI), and immune (CRP, WBC, albumin) domains. An exposome score was derived via bifactor analysis of 61 (UKB) and 11 (AoU) baseline exposures spanning diet, lifestyle, neighborhood, and psychosocial factors. Propensity score matching controlled for age, sex, race/ethnicity, and socioeconomic indicators. Mediation analysis estimated indirect effects of exposome on EoC operating through AL. Results: Mean age was 43.0 years in UKB and 39.8 years in AoU; 72.5-76.5% were female. For each SD increase in baseline AL, there was 11-18% increased odds of subsequent EoC (AoU OR: 1.18 95%CI 1.12-1.24; UKB OR: 1.11 1.04-1.18). Exposome score was significantly associated with AL (AoU β=0.09; UKB β=0.08; both p<0.001). Mediation analyses revealed significant indirect effects in both cohorts, with non-significant direct effects (Table). For exposome-related cancers, AL mediated 8.7-15.4% of exposomic risk. Conclusions: This is the first multinational population-level study to demonstrate that AL mediates environmental risk pathways to EoC, supporting the hypothesis that cumulative environmental burden promotes carcinogenesis through physiological stress pathways. AL represents a potentially modifiable target for EoC risk stratification. Future research integrating polygenic risk and longitudinal exposome assessments may refine mechanistic understanding and enable precision prevention approaches for this growing public health challenge. Mediation of exposome-EoC association via AL. Cohort Cancer Group Indirect Effect* (p) Direct Effect # (p) Proportion Mediated (p) AoU All 0.005 (<0.001) −0.012 (0.14) − AoU Exposome-Related 0.001 (<0.001) 0.007 (0.06) 15.4% (0.02) UKB All 0.002 (<0.001) −0.005 (0.63) − UKB Exposome-Related 0.001 (0.01) 0.008 (0.17) 8.7% (0.14) *β of exposome-EoC effect operating through AL. # β of exposome-EoC effect independent of AL. Exposome-related cancers: colorectal, lung, liver, bladder, upper GI.
Parikh et al. (Wed,) studied this question.