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

ABSTRACT 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.