Developmental timing distinguishes pediatric and adult cancers through retention and rewiring mechanisms

Abstract

Abstract Oncogenic mutations can have fundamentally different consequences depending on the developmental state of the tissue in which they arise. We propose a unifying model in which early-life oncogenic events promote retention, stabilization of transient embryo-fetal transcriptional and epigenetic programs, whereas later-life mutations more often require rewiring, reactivating suppressed oncofetal states through stepwise transcriptional and chromatin remodeling. This temporal dimension helps explain why childhood and adult cancers can follow distinct lineage trajectories, behaviors, and therapeutic responses, even when initiated by the same genetic lesion. Incorporating developmental timing into cancer modeling and risk stratification may improve prognostic resolution and reveal stage-specific vulnerabilities.