Rare germline structural variants increase risk for pediatric solid tumors

• 成果类型: Article
• 署名作者: Gillani, Riaz; Collins, Ryan L.; Crowdis, Jett; Garza, Amanda; Jones, Jill K.; Walker, Mark; Sanchis-Juan, Alba; Whelan, Christopher W.; Pierce-Hoffman, Emma; Talkowski, Michael E.; Brand, Harrison; Haigis, Kevin; LoPiccolo, Jaclyn; AlDubayan, Saud H.; Gusev, Alexander; Crompton, Brian D.; Janeway, Katherine A.; Van Allen, Eliezer M.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; King Saud Bin Abdulaziz University for Health Sciences; Harvard University; Harvard T.H. Chan School of Public Health; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9941
• DOI: 10.1126/science.adq0071
• 发表日期: 2025-01-03
• 关键词: copy number variation; cancer; predisposition; heritability; association; landscape; map; disorders; mutations; DISCOVERY

摘要

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.