对 1220 例癌症进行高覆盖全基因组分析，揭示了数百个因重排介导的顺式调控改变而失调的基因。
High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations.
机构信息
Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
European Molecular Biology Laboratory, European Bioinformatics Institute, (EMBL-EBI), Cambridge, UK.
出版信息
Nat Commun. 2020 Feb 5;11(1):736. doi: 10.1038/s41467-019-13885-w.
The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
体细胞结构变异（SVs）对癌症中基因表达的影响在很大程度上是未知的。在这里，作为 ICGC/TCGA 全基因组泛癌分析（PCAWG）联盟的一部分，该联盟聚合了来自 1220 例常见癌症病例的全基因组测序数据和 RNA 测序数据，我们报告了数百个基因，这些基因的 SV 断点附近存在与表达改变相关。对于这些基因中的大多数，表达增加而不是减少与相应的断点事件相关。受此现象影响的上调的癌症相关基因包括 TERT、MDM2、CDK4、ERBB2、CD274、PDCD1LG2 和 IGF2。TERT 相关的断点涉及约 3%的病例，最常见于肝胆管、黑色素瘤、肉瘤、胃和肾肿瘤。与 PD1 和 PDL1 基因上调相关的 SV 涉及约 1%的非扩增病例。对于许多基因，SV 与基因附近增强子调控元件数量的增加或更接近显著相关。启动子附近的 DNA 甲基化通常随着附近 SV 断点的增加而增加，这可能涉及抑制元件的失活。
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