Camilla Giovino1,2,5, Vallijah Subasri1,2,5, Frank Telfer1,2,5 and David Malkin1,2,3,4 1Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada 2Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada 3Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada 4Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada Correspondence: david.malkinsickkids.ca

↵5 These authors contributed equally to this work.

Approximately 8.5%–16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant—a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li–Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning–based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention.