Germline variation in DNA damage repair genes in children with cancer: Unveiling SMARCAL1 as novel osteosarcoma predisposition gene

BackgroundRecent large-scale genomic sequencing studies reveal that 5-18% of children with cancer harbor pathogenic variants (PV) in known cancer predisposing genes (CPG). However, DNA damage repair (DDR) genes, which are frequently somatically altered in pediatric tumors, have not been systematically examined as a source of novel cancer predisposing signals. MethodsTo address this gap, we interrogated 189 genes across six DDR pathways for the presence of PV among 5,993 childhood cancer cases and 14,477 adult non-cancer controls. PV were defined as rare (allele frequency 0.7. Using logistic and firth regression, we identified genes with statistically enriched PV and replicated findings among 1,494 additional childhood cancer cases across three independent cohorts. FindingsAnalysis across all cancers revealed enrichment of TP53 PV (0.6%, false discovery rate [FDR]logistic=0.0066, FDRFirth=0.0064). Cancer-specific analyses confirmed previously identified associations for germline TP53 PV in adrenocortical carcinoma (37%, FDRlogistic<0.0001, FDRFirth=0) and high-grade glioma (2.4%, FDRlogistic=0.0022, FDRFirth=0.1082), as well as BARD1 PV in neuroblastoma (1.2%, FDRlogistic=0.0341, FDRFirth=0.2682). Three novel gene-tumor associations were identified, including POLL PV in Ewing sarcoma (1.7%, FDRlogistic=0.0319, FDRFirth=0.3101), SMC5 PV in medulloblastoma (1.6%, FDRlogistic=0.0005, FDRFirth=0.0499) and SMARCAL1 PV in osteosarcoma (2.6%, FDRlogistic=0.0250, FDRFirth=0.2180). Among these putative CPG, SMARCAL1 PV were enriched in osteosarcoma across each of the replication pediatric cancer cohorts (2.5%, PFisher <0.0001). All three osteosarcomas with available tumor data exhibited deletion of the wild-type SMARCAL1 allele. InterpretationOur study identifies SMARCAL1 PV as a predisposing factor for osteosarcoma, providing insights into tumor biology and creating opportunities for development of novel therapeutic, surveillance, and preventive interventions for this aggressive childhood cancer.