Comprehensive investigation of DNA damage repair genes in children with cancer identifies as novel osteosarcoma predisposition gene.

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 PV (0.6%, false discovery rate [FDR]=0.0066, FDR=0.0064). Cancer-specific analyses confirmed previously identified associations for germline PV in adrenocortical carcinoma (37%, FDR<0.0001, FDR=0) and high-grade glioma (2.4%, FDR=0.0022, FDR=0.1082), as well as PV in neuroblastoma (1.2%, FDR=0.0341, FDR=0.2682). Three novel gene-tumor associations were identified, including PV in Ewing sarcoma (1.7%, FDR=0.0319, FDR=0.3101), PV in medulloblastoma (1.6%, FDR=0.0005, FDR=0.0499) and PV in osteosarcoma (2.6%, FDR=0.0250, FDR=0.2180). Among these putative CPG, PV were enriched in osteosarcoma across each of the replication pediatric cancer cohorts (2.5%, P <0.0001). All three osteosarcomas with available tumor data exhibited deletion of the wild-type allele.

INTERPRETATION

Our study identifies 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.