METB-09. GERMLINE PATHOGENIC VARIANTS IN 838 PEDIATRIC BRAIN TUMOR PATIENTS

The genetic contribution of rare pathogenic germline variation in cancer patients without a family history remains unclear. We sought to characterize the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in pediatric brain tumor patients. Paired tumor and normal whole genome or exome sequencing was performed for 838 patients in the Pediatric Brain Tumor Atlas (PBTA). Rare variants in 196 CPGs were annotated as pathogenic (P) or likely pathogenic (LP) in an automated manner consistent with American College of Medical Genetics criteria and reviewed by an interdisciplinary panel. To assess enrichment, the frequency of CPG P-LP variants in cases was compared to the gnomAD v3.1 cancer-free control cohort (n=74,023). Second hit, mutational signature, and gene set enrichment analyses (GSEA) were performed on matched tumor sequencing to characterize differences in patients with and without germline P-LP variants in DNA repair genes. We observed 178 germline CPG P-LP variants in 163 PBTA patients (19.5%). CPG P-LP variants were most prevalent among Neurofibroma plexiform patients (64.3%), and NF1 and TSC2 harbored the most significant P-LP variant burden compared to controls (OR=69.5, p=2.4E-23, CI=34.6-137 and OR=357, p=1.1E-14, CI=71-3669, respectively). DNA repair gene P-LP variants were enriched in cases compared to controls (OR=4.4, p=8.3E-30). Patients harboring mismatch repair (MMR) gene P-LP variants exhibited significantly higher tumor-associated MMR-deficiency mutational signature exposures (p<0.05) and DNA repair GSEA scores relative to other patients (p=0.04). Second hit SNVs in tumors were identified in four patients with P-LP germline variants in NF1 (n=2), APC (n=1), and SUFU (n=1). Germline P-LP variants are enriched in PBTA patients, and DNA repair variants are predictive of repair-deficiency signatures in tumor samples. Our work emphasizes the need for germline sequencing to inform patient care.