Rare germline structural variants increase risk for pediatric solid tumors.

Science (New York, N.Y.)
Authors
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.

Year of Publication
2025
Journal
Science (New York, N.Y.)
Volume
387
Issue
6729
Pages
eadq0071
Date Published
01/2025
ISSN
1095-9203
DOI
10.1126/science.adq0071
PubMed ID
39745975
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