Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, 3615 Civic Center Blvd Abramson Building, Philadelphia, PA, 19104, USA.
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Mol Cancer. 2023 Aug 5;22(1):126. doi: 10.1186/s12943-023-01828-5.
Children with birth defects (BD) express distinct clinical features that often have various medical consequences, one of which is predisposition to the development of cancers. Identification of the underlying genetic mechanisms related to the development of cancer in BD patients would allow for preventive measures. We performed a whole genome sequencing (WGS) study on blood-derived DNA samples from 1566 individuals without chromosomal anomalies, including 454 BD probands with at least one type of malignant tumors, 767 cancer-free BD probands, and 345 healthy individuals. Exclusive recurrent variants were identified in BD-cancer and BD-only patients and mapped to their corresponding genomic regions. We observed statistically significant overlaps for protein-coding/ncRNA with exclusive variants in exons, introns, ncRNAs, and 3'UTR regions. Exclusive exonic variants, especially synonymous variants, tend to occur in prior exons locus in BD-cancer children. Intronic variants close to splicing site (< 500 bp from exon) have little overlaps in BD-cancer and BD-only patients. Exonic variants in non-coding RNA (ncRNA) tend to occur in different ncRNAs exons regardless of the overlaps. Notably, genes with 5' UTR variants are almost mutually exclusive between the two phenotypes. In conclusion, we conducted the first genomic study to explore the impact of recurrent variants exclusive to the two distinguished clinical phenotypes under study, BD with or without cancer, demonstrating enrichment of selective protein-coding/ncRNAs differentially expressed between these two phenotypes, suggesting that selective genetic factors may underlie the molecular processes of pediatric cancer development in BD children.
患有出生缺陷 (BD) 的儿童表现出明显的临床特征，这些特征往往有各种医学后果，其中之一是易患癌症。确定与 BD 患者癌症发展相关的潜在遗传机制将允许采取预防措施。我们对来自 1566 名无染色体异常个体的血液衍生 DNA 样本进行了全基因组测序 (WGS) 研究，包括 454 名至少有一种恶性肿瘤的 BD 先证者、767 名无癌症的 BD 先证者和 345 名健康个体。在 BD-癌症和 BD 患者中鉴定了独特的复发性变异，并将其映射到相应的基因组区域。我们观察到具有独特变异的蛋白质编码/非编码 RNA 在exon、intron、ncRNA 和 3'UTR 区域的重叠具有统计学意义。独特的外显子变异，特别是同义变异，往往发生在 BD-癌症儿童的先前exon 位置。靠近剪接位点的内含子变异（距exon 小于 500bp）在 BD-癌症和 BD 患者中重叠很少。非编码 RNA (ncRNA) 中的外显子变异倾向于发生在不同的 ncRNA 外显子中，无论重叠与否。值得注意的是，5'UTR 变异的基因在这两种表型之间几乎是相互排斥的。总之，我们进行了第一项基因组研究，以探讨仅在两种有区别的临床表型（有或无癌症的 BD）下发生的复发性变异的影响，这些表型表现出这些表型之间差异表达的选择性蛋白质编码/非编码 RNA 的富集，表明选择性遗传因素可能是 BD 儿童癌症发展的分子过程的基础。
