Comprehensive investigation of DNA damage repair genes in children with cancer identifies SMARCAL1 as novel osteosarcoma predisposition gene
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Background
Recent 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.
Methods
To 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 <0.05% in the gnomAD v2.1 non-cancer subset), nonsense, frameshift, affecting canonical splice sites, and missense with REVEL score >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.
Findings
Analysis across all cancers revealed enrichment of TP53 PV (0.6%, false discovery rate [FDR] logistic =0.0066, FDR Firth =0.0064). Cancer-specific analyses confirmed previously identified associations for germline TP53 PV in adrenocortical carcinoma (37%, FDR logistic <0.0001, FDR Firth =0) and high-grade glioma (2.4%, FDR logistic =0.0022, FDR Firth =0.1082), as well as BARD1 PV in neuroblastoma (1.2%, FDR logistic =0.0341, FDR Firth =0.2682). Three novel gene-tumor associations were identified, including POLL PV in Ewing sarcoma (1.7%, FDR logistic =0.0319, FDR Firth =0.3101), SMC5 PV in medulloblastoma (1.6%, FDR logistic =0.0005, FDR Firth =0.0499) and SMARCAL1 PV in osteosarcoma (2.6%, FDR logistic =0.0250, FDR Firth =0.2180). Among these putative CPG, SMARCAL1 PV were enriched in osteosarcoma across each of the replication pediatric cancer cohorts (2.5%, P Fisher <0.0001). All three osteosarcomas with available tumor data exhibited deletion of the wild-type SMARCAL1 allele.
Interpretation
Our 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.
