Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis
Genomic features of renal cell carcinoma developed during end-stage renal disease and dialysis
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DOI：
10.1093/hmg/ddac180
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发表时间：
2022-08-18
影响因子：
3.5
通讯作者：
Nakagawa, Hidewaki
中科院分区：
文献类型：
--
作者：
Johnson, Todd A.;Maekawa, Shigekatsu;Nakagawa, Hidewaki
患有终末期肾病（ESRD）或接受透析的患者患肾细胞癌（RCC）的风险要高得多，但致癌机制和基因组特征仍然很少探索和不确定。本研究的目的是确定ESRD RCC的基因组特征，并将其与肿瘤组织学和透析暴露相关。在这项研究中，我们获得了33个RCC，具有不同的组织学亚型，在接受透析的ESRD患者中发展，并进行了全基因组测序和转录组分析。使用整合来自种系和体细胞SNV、Indel和结构变体以及CNA的数据的分析管道进行驱动事件、拷贝数改变（CNA）分析和突变特征谱分析，同时通过基因集富集分析来分析差异表达基因的转录组数据。ESRD相关透明细胞RCC的驱动基因和突变反映了散发性ccRCC中的驱动基因和突变。较长的透析时间与罕见的突变特征SBS 23（其病因不明）和线粒体拷贝数增加显著相关。所有获得性囊性疾病（ACD）-RCC，这是专门在ESRD患者中发展，显示染色体16 q扩增。基因表达分析表明某些ACD-RCC和乳头状RCC之间的相似性，以及在具有16号染色体的TCGA乳头状RCC中，获得了与DNA修复相关的基因的鉴定富集，以及与活性氧、氧化磷酸化和Myc靶点相关的途径。该分析表明，ESRD或透析可能诱导细胞应激类型，影响某些特定类型的基因组损伤，导致肿瘤发生。
Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study's goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses. Driver events, copy-number alteration (CNA) analysis and mutational signature profiling were performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels and structural variants as well as CNAs, while transcriptome data were analyzed for differentially expressed genes and through gene set enrichment analysis. ESRD related clear cell RCCs' driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All acquired cystic disease (ACD)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation and targets of Myc. This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis.