Germline Cancer Predisposition and De Novo Contributions in Pediatric Rhabdomyosarcoma: A Report From the Children's...

Approximately 6%-8% of children and adolescents with rhabdomyosarcoma (RMS) have an underlying cancer predisposition disorder (CPD), which varies between embryonal and alveolar subtypes and other clinical characteristics. Identifying a CPD remains challenging, as traditional approaches rely on clinical features and family history. Additionally, the contribution of de novo germline pathogenic variants (GPVs) to RMS etiology remains uncharacterized, and the presence of de novo GPVs, variable expressivity, or incomplete penetrance may limit clinical recognition of at-risk individuals. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is a tool proposed to help clinicians identify patients with increased likelihood of a CPD by incorporating tumor-specific referral criteria. The Children's Oncology Group (COG) Genetics of Embryonal and Alveolar Rhabdomyosarcoma Study (GEARS; AEPI15N1) enrolled families of 299 children and young adults with RMS. In addition to collection of questionnaires, germline samples were collected from probands and family members for whole genome sequencing (WGS). GPVs in CPD genes were identified in 10.6% of probands and more commonly in patients with embryonal versus alveolar tumors (12.0% vs. 7.8%, respectively; p = 0.372). Through WGS analysis of proband-parent trios, 30.0% of GPVs were classified as de novo. The MIPOGG algorithm correctly identified 85.7% of children with RMS and a GPV, but specificity was limited (43.0%). Germline CPD identification has important clinical implications, and these findings highlight the utility and limitations of decision-support tools like MIPOGG. This emphasizes the need to refine CPD screening methods to inform risk assessments and guide genetic evaluation and counseling in children with RMS.