Rare germline structural variants increase risk for pediatric solid tumors

Science. 2025 Jan 3;387(6729):eadq0071. doi: 10.1126/science.adq0071. Epub 2025 Jan 3.

Abstract

Pediatric solid tumors are a leading cause of childhood disease mortality. In this work, we examined germline structural variants (SVs) as risk factors for pediatric extracranial solid tumors using germline genome sequencing of 1765 affected children, their 943 unaffected parents, and 6665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we uncovered burdens of ultrarare SVs that cause loss of function of highly expressed, mutationally constrained genes, as well as noncoding SVs predicted to disrupt chromatin domain boundaries. Collectively, we estimate that rare germline SVs explain 1.1 to 5.6% of pediatric cancer liability, establishing them as an important component of disease predisposition.

MeSH terms

  • Adult
  • Bone Neoplasms* / genetics
  • Child
  • Child, Preschool
  • Chromatin / genetics
  • Chromosome Aberrations
  • Female
  • Genetic Predisposition to Disease*
  • Genomic Structural Variation*
  • Germ-Line Mutation*
  • Humans
  • Loss of Function Mutation
  • Male
  • Neuroblastoma* / genetics
  • Risk Factors
  • Sarcoma, Ewing* / genetics
  • Sex Factors

Substances

  • Chromatin