儿科癌症有两个关键特征：(a) 种系改变的发生率较高；(b) 改变类型的异质性。最近的基于人群的评估表明，即使没有染色体异常，有出生缺陷（BD）的儿童也更有可能患癌症；因此，对患有 BD 和癌症的儿童的基因改变的探索可以为儿童肿瘤发展的潜在机制提供新的见解。我们对 1556 名无染色体异常的个体的血液来源 DNA 进行了全基因组测序 (WGS)，其中包括 454 名患有至少一种恶性肿瘤的 BD 先证者、757 名患有 BD 的无癌症儿童和 345 名健康个体，重点关注拷贝数量变异（CNV）分析。大约一半患有 BD 癌症的儿童具有在仅 BD/健康个体中未发现的 CNV，并且 CNV 在这些患者中分布不均匀。观察到强烈的异质性，在超过 3 名患者中含有 CNV 的癌症易感基因数量有限。此外，CNV基因的功能富集表明，数十名患者存在与相同生物学途径相关的变异，例如具有神经功能的基因的缺失和免疫反应基因的重复。表型聚类揭示了肉瘤患者的复发：观察到非编码 RNA 调节因子显着富集，在功能分析中显示出与生长和癌症调节相关的强烈信号。总之，我们进行了首批基因组研究之一，探索 CNV 对 BD 儿童癌症发展的影响，揭示了对潜在生物过程的新见解。© 2024 作者。约翰·威利出版的《分子肿瘤学》

There are two key signatures of pediatric cancers: (a) higher prevalence of germline alterations and (b) heterogeneity in alteration types. Recent population-based assessments have demonstrated that children with birth defects (BDs) are more likely to develop cancer even without chromosomal anomalies; therefore, explorations of genetic alterations in children with BDs and cancers could provide new insights into the underlying mechanisms for pediatric tumor development. We performed whole-genome sequencing (WGS) on blood-derived DNA for 1556 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumor, 757 cancer-free children with BDs, and 345 healthy individuals, focusing on copy number variation (CNV) analysis. Roughly half of the children with BD-cancer have CNVs that are not identified in BD-only/healthy individuals, and CNVs are not evenly distributed among these patients. Strong heterogeneity was observed, with a limited number of cancer predisposition genes containing CNVs in more than three patients. Moreover, functional enrichments of genes with CNVs showed that dozens of patients have variations related to the same biological pathways, such as deletions of genes with neurological functions and duplications of immune response genes. Phenotype clustering uncovered recurrences of patients with sarcoma: A notable enrichment was observed involving non-coding RNA regulators, showing strong signals related to growth and cancer regulations in functional analysis. In conclusion, we conducted one of the first genomic studies exploring the impact of CNVs on cancer development in children with BDs, unveiling new insights into the underlying biological processes.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.