Abstract Purpose: The role of germline predisposition in pediatric cancer is increasingly recognised. However, the optimal approach to identifying cancer predisposing germline pathogenic variants (GPV) in children, and even the prevalence of GPV among children with cancer, remain unclear. We examined GPV prevalence, and diagnostic yield of different test approaches, within a national paediatric 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 GPV 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 recognised phenotypic spectrum for 43.7% of reported GPV, 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 GPV, and provided biological insight into tumor etiology, together highlighting the value of integrated analyses. Cascade testing in first-degree relatives confirmed the GPV was de novo in 21% of tested families. Within inherited GPV (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 GPV in children with poor-prognosis cancers and their first-degree relatives.
Fuentes-Bolanos et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: