Bridging the gap: integrating hereditary cancer into precision oncology

Advances in next-generation sequencing have expanded the identification of hereditary cancer patients, which account for approximately 10% of all cancer diagnoses. Precision medicine has profoundly reshaped the landscape of oncology, particularly in the management of hereditary cancer syndromes, through the convergence of germline genetics and targeted therapeutics. Disruption of homologous recombination repair genes such as BRCA1/2 and PALB2 confers synthetic lethal sensitivity to Poly ADP-ribose polymerase inhibitors and combination strategies targeting replication stress or cell-cycle checkpoints. Mismatch repair deficiency results in microsatellite instability and an increased neoantigen load, enabling durable responses to immune checkpoint blockade and supporting organ-preserving approaches in selected localized settings. Germline VHL inactivation induces a constitutive pseudohypoxic state that can be therapeutically exploited with HIF2α inhibitors in von Hippel-Lindau-associated neoplasms, illustrating interception of a lineage-agnostic metabolic axis. Activating germline RET pathogenic variants in hereditary medullary thyroid carcinoma demonstrate how highly selective kinase inhibitors can achieve superior efficacy-toxicity profiles compared with earlier multikinase agents. In patients with neurofibromatosis type 1, dysfunction of the neurofibromin GTPase-activating protein leads to RAS pathway hyperactivation, defining a rational therapeutic target. This evolving paradigm underscores the expanding role of germline testing beyond individuals with strong personal or family histories of cancer. Timely and equitable access to genetic results is essential to ensure that patients benefit from precision therapies without unnecessary delays. This review provides an integrative framework for bridging hereditary cancer and precision oncology.