Investigation of DNA Damage Response Genes Validates the Role of DNA Repair in Pediatric Cancer Risk and Identifies <i>SMARCAL1</i> as a Novel Osteosarcoma Predisposition Gene.

ABSTRACT:

Purpose

Recent studies reveal that 5%-18% of children with cancer harbor pathogenic variants in known cancer-predisposing genes. 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 DDR genes for presence of germline predisposing variants (PV) among 5,993 childhood cancer cases and 14,477 adult noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germ

SUBMITTER: Oak N 

PROVIDER: S-EPMC12643103 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature