Evaluating the Utility of Paired Tumor and Germline Targeted DNA Sequencing for Pediatric Oncology Patients: A Single Institution Report

OBJECTIVE: To evaluate the diagnostic yield and utility of universal paired tumor-normal multigene panel sequencing in newly diagnosed pediatric solid and central nervous system (CNS) tumor patients and to compare the detection of germline pathogenic/likely pathogenic variants (PV/LPVs) against established clinical referral criteria for cancer predisposition assessment. METHODS: From May 2021 to November 2022, all patients with newly diagnosed and previously untreated CNS and non-CNS solid tumors who had planned ongoing oncology care at Seattle Children's Hospital were offered paired tumor-normal targeted next-generation sequencing (NGS) using the UW-OncoPlex cancer gene panel, versions 6, 7, and 8. Known variant testing was offered to a subset of parents whose child was identified to carry a PV/LPV in a cancer susceptibility gene (CSG). Participant data was retrospectively reviewed based on the most utilized pediatric cancer predisposition screening tools to determine whether a patient met clinical criteria for referral for genetic assessment. RESULTS: A total of 193 patients were eligible for sequencing. A number of 158/193 (82%) patients underwent paired tumor-normal sequencing. Twenty-eight (17.7%) patients tested positive for a PV/LPV in a CSG. Ten (6.3%) patients had a P/LPV in a CSG associated with adult-onset cancer risks. Four of 28 (14.2%) patients with a PV/LPV in a CSG would have been missed by phenotype or family history-based referral criteria. CONCLUSIONS: Paired tumor-normal multigene panel testing of pediatric tumors remains an unbiased method of capturing patients with an underlying cancer predisposition syndrome that may otherwise go undetected with more selective screening tools.