Accelerating Cancer Risk Factor Discovery for Prevention in Younger Generations

The global incidence of early-onset cancer, diagnosed before age 50, is rising, with pronounced birth cohort effects. This alarming trend underscores an urgent need to accelerate discovery of novel cancer risk factors and their underlying biological networks, and to translate these insights into prevention and interception strategies that protect future generations. In this Perspective, we summarize key milestones and outline conceptual, methodological, and resource-related challenges that are hindering progress. To address these gaps, we propose three interconnected frameworks that extend traditional epidemiologic approaches: (1) a tissue-ecosystem anchored, critical window-aware framework for cancer risk factor discovery; (2) a life course informed, biological state-based framework for precision cancer risk assessment; and (3) an integrated, dynamic, natural history-based framework to characterize cancer preventability. Together, they offer an initial roadmap for connecting exposures to molecular changes across biological scales, life stages, and populations to reveal the networks of causal risk factors. By beginning to map when and where risk factors disrupt shared hallmarks of cancer, reflected in shifts in (epi)genetic, immune, metabolic, and microbial pathways, these approaches can start to inform biologically grounded, scalable strategies to prevent cancer and other chronic diseases.