Clinical criteria for genetic testing in pediatric oncology show a low specificity and miss every 4^thchild carrying a cancer predisposition

AbstractClinical checklists are the current gold standard to determine whether a child with cancer shows indications for genetic testing. Nevertheless, the efficacy of these tests to reliably detect genetic cancer predisposition in children with cancer is still insufficiently investigated. Here, we assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding whole exome sequencing analysis in an unselected single-center cohort of 139 child-parent datasets. We applied a strict testing to only include autosomal dominant or compound heterozygous cancer-related variants.Our study reflects a high consent rate for genetic testing (>90%). In total, 1/3rdof patients had a clinical indication for genetic testing according to current recommendations and 10.8% (n=15/139) of children harbored a proven cancer predisposition based on exome sequencing. Out of these only 73.3% (n=11/15) were identified through the clinical checklist. In addition, >2 clinical findings in the applied checklist increased the likelihood to identifying genetic predisposition from 15% to 50%. While our data revealed a high rate of genetic predisposition (50%, n=5/10) in Myelodysplastic Syndrome (MDS) cases, no cancer predisposition variants were identified in the sarcoma and lymphoma group.In summary, our data showed a low checklist specificity of 68.5%, and missed every 4thchild with genetic predisposition. This highlights the drawbacks of sole clinical evaluation to accurately identify all children at risk and underlines the need for routine germline sequencing of pediatric cancers.