Allostatic load as a potential pathway linking exposomic risk to early-onset cancer: a matched case-control study in the All of Us Research Program

Background: Early-onset cancer (EoC) incidence is rising worldwide, yet risk models built on isolated exposures or rare pathogenic variants capture little of the cumulative environmental burden experienced by younger adults. Allostatic load (AL), the cumulative physiological burden of chronic stress, can be measured from routine laboratory values and vital signs and is a candidate biological pathway linking environmental exposures to carcinogenesis. Methods: We conducted a 1:4 matched case-control study nested within the NIH All of Us Research Program, including 7,550 participants and 1,510 cancers diagnosed before age 50, of which 298 were exposome-related (the primary outcome). We derived an exposomic risk score (ERS) from 12 survey-based measures and an eight-component AL score from electronic health record data, and used mediation analysis to estimate the proportion of the ERS-EoC association operating through AL. Results: A higher ERS was associated with higher AL (β=0.18 standard deviations [SD] per SD; 95% CI 0.16-0.20), and each SD increase in AL was associated with 21% higher odds of EoC (odds ratio 1.21; 95% CI 1.15-1.28). For exposome-related EoC, AL mediated 17.0% (95% CI 7.4-49.5%) of the association between the ERS and EoC, with significant total, direct, and indirect effects that were robust to lag, scoring, and age-adjustment sensitivity analyses. Across all EoC, the proportion mediated was 48.8% (95% CI 21.2-186.5%). Conclusions: AL is a candidate biomarker and potential pathway through which cumulative environmental burden relates to EoC, warranting prospective validation in independent cohorts.