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PURPOSE: The role of germline predisposition in pediatric cancer is increasingly recognized. However, the optimal approach to identifying cancer predisposing germline pathogenic variants (GPV) in children, and even the prevalence of GPVs among children with cancer, remain unclear. We examined GPV prevalence and diagnostic yield of different test approaches within a national pediatric precision oncology program.EXPERIMENTAL DESIGN: We performed prospective rapid-turnaround whole-genome and -transcriptome profiling of 496 consecutively recruited children with poor-prognosis cancer to identify genetic variants linked to cancer risk.RESULTS: Integration of tumor and germline molecular profiling identified GPVs in 15.5% of patients, an incremental GPV yield of 7.9% above that detected by standard care. Although the cancer type was outside the recognized phenotypic spectrum for 43.7% of reported GPVs, 63.2% of these were clinically actionable. Integrated germline-tumor analysis increased the GPV detection rate by 8.5%, informed germline interpretation in 14.3% of patients with GPVs, and provided biological insight into tumor etiology, together highlighting the value of integrated analyses. Cascade testing in first-degree relatives confirmed that the GPV was de novo in 21% of tested families. Within inherited GPVs (73.9%), 47.8% had direct implications for risk management recommendations in the relevant parent.CONCLUSIONS: Our findings establish the clinical benefit and feasibility of integrated tumor-germline whole-genome screening to detect GPVs in children with poor-prognosis cancers and their first-degree relatives.