iPSC models of hereditary cancer predisposition: Mechanistic insights into premalignant evolution and lineage-specific vulnerability.

Hereditary cancer carrier tissues are difficult to sample before transformation, limiting direct study of early disease evolution. Induced pluripotent stem cells (iPSCs) preserve inherited genetic context and enable controlled reconstruction of susceptible lineages and defined second hits. Across hereditary breast and ovarian cancer, mismatch repair deficiency, Li-Fraumeni syndrome and familial adenomatous polyposis, current evidence is strongest but uneven for BRCA1/2/PALB2-, MMR-, TP53- and APC-associated models. Collectively, these systems show that lineage state, contextual stress and acquired second hits shape DNA-repair defects, clonal selection and premalignant evolution. However, developmental immaturity, incomplete stromal and immune context, clonal drift and protocol variability constrain interpretation. iPSC models should therefore be used as mechanistic filters for testing causality, comparing lineage vulnerability and prioritising biomarkers or prevention hypotheses, rather than as stand-alone predictors of individual cancer risk or clinical outcome. Their outputs require validation in adult tissues, patient-derived models and carrier cohorts.