Allostatic load as a mediator of exposomic risk pathways to early-onset cancer: A cross-cohort validation study.

作者：Ravi B. Parikh, Anthony Girard, Tyler M. Moore, Elina Visocki, Timothy Bigdeli, Sinan Gülöksüz, Lauren E. McCullough, Katherine L. Nathanson, Ran Barzilay · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.16_suppl.10500 · 研究领域：Health, Environment, Cognitive Aging、Nutrition, Genetics, and Disease、Cancer Risks and Factors

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: 1.1...