The Diagnostic Yield of Panel Versus Exome Sequencing to Identify Hereditary Cancer Disorders in Pediatric Cancer.

Abstract

This study aimed to assess whether targeted exome sequencing (TES) outperforms next- generation sequencing (NGS) panels in detecting clinically actionable cancer predisposition syndromes (CPS) in pediatric cancer patients. Patients with cancer underwent genetic counseling and NGS panel testing (27 or 64 genes). Simultaneously, a 616-gene targeted exome, including the NGS panel genes and 552 additional potential cancer-related genes, was conducted on the patients and their parents. Out of 42 patients undergoing both tests, NGS panels identified an APC risk allele (RA) in a patient with ganglioglioma and a pathogenic RB1 variant in a patient with retinoblastoma. In addition to the variants found by NGS panels, TES detected a pathogenic MUTYH variant in a patient with acute lymphoblastic leukemia (ALL) and a likely pathogenic (LP) BLM variant in another patient with ALL. TES also revealed a variant in candidate CPS genes, MC1R (RA) and EXT2 (LP), in a patient with embryonal rhabdomyosarcoma and Ewing sarcoma, respectively. Despite identifying variants in candidate CPS genes (MC1R, EXT2) not included on common NGS panels and known CPS genes (MUTYH, BLM) absent from this study's panels, the diagnostic yield of clinically actionable CPS variants did not substantially increase with TES compared with standard NGS panels in pediatric cancer patients. In conclusion, for most cases, panel testing remains appropriate for CPS diagnosis in pediatric cancer within typical clinical settings.