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
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Science. 2025 Jan 3;387(6729):eadq0071. doi: 10.1126/science.adq0071.
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.
小儿实体瘤是儿童疾病死亡的主要原因。在这项研究中，我们通过对1765名患病儿童、943名未患病父母和6665名成年对照进行种系基因组测序，研究了种系结构变异（SVs）作为小儿颅外实体瘤的风险因素。我们发现，非常大（>1兆碱基）的种系染色体异常与男性儿童实体瘤风险增加之间存在性别偏向性关联。种系SVs的总体影响在神经母细胞瘤中最为显著，我们在其中发现了超罕见SVs的负担，这些SVs导致高表达、受突变限制的基因功能丧失，以及预计会破坏染色质结构域边界的非编码SVs。总体而言，我们估计罕见的种系SVs可解释1.1%至5.6%的小儿癌症易感性，将它们确立为疾病易感性的重要组成部分。
