Von Hippel-Lindau（VHL）病是一种常染色体显性遗传肿瘤综合征，发病率约为1/36,000。与VHL病相关的透明细胞肾细胞癌（ccRCC）是最常见的先天性肾细胞癌。尽管近年来治疗肾细胞癌的进展提高了患有VHL病的患者的长期预后，但肾癌仍然是这些患者的主要死亡原因。因此，寻找VHL病相关的ccRCC的诊断和治疗新靶点仍然至关重要。 在本研究中，我们收集了北京大学第一医院泌尿外科诊断和手术治疗的25名VHL病相关ccRCC患者的配对肿瘤组织和正常样本。经过筛选，我们对23对组织进行了全基因组亚硫酸酯测序（WGBS）和6对组织进行了RNA-seq。并且我们还将VHL病相关的ccRCC转录组数据与来自The Cancer Genome Atlas（TCGA）公共数据库的散发性ccRCC转录组数据进行了比较 结果：我们发现VHL病相关ccRCC肿瘤组织的甲基化水平显著低于正常组织。与正常组织相比，肿瘤组织在3p缺失和5q、7q增益的拷贝数方面存在差异。我们整合了RNA-seq和WGBS数据，揭示了与VHL病相关ccRCC相关的甲基化候选基因；我们的结果显示了124个过甲基化和下调基因，以及245个低甲基化和上调基因。通过将VHL病相关ccRCC转录组数据与TCGA公共数据库中的散发性ccRCC转录组数据进行比较，我们发现差异基因富集的主要通路在两者之间有所不同。 我们的研究绘制了VHL综合征下透明细胞肾细胞癌肿瘤和正常组织的拷贝数变异、甲基化和mRNA水平变化的多组学图谱，为透明细胞肾细胞癌机制研究、生物标志物筛选和治疗靶点发现提供了坚实基础。 © 2023. 作者, 排他性授权给 Springer Nature Switzerland AG。

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumor syndrome with an incidence of approximately 1/36,000. VHL disease-associated clear cell renal cell carcinoma (ccRCC) is the most common congenital RCC. Although recent advances in treating RCC have improved the long-term prognosis of patients with VHL disease, kidney cancer is still the leading cause of death in these patients. Therefore, finding new targets for diagnosing and treating VHL disease-associated ccRCC is still essential.In this study, we collected matched tumor tissues and normal samples from 25 patients with VHL disease-associated ccRCC, diagnosed and surgically treated in the Department of Urology, Peking University First Hospital. After screening, we performed whole genome bisulfite sequencing (WGBS) on 23 pairs of tissues and RNA-seq on 6 pairs of tissues. And we also compared the VHL disease-associated ccRCC transcriptome data with the sporadic ccRCC transcriptome data from the The Cancer Genome Atlas (TCGA) public database RESULTS: We found that the methylation level of VHL disease-associated ccRCC tumor tissues was significantly lower than that of normal tissues. The tumor tissues showed a difference in the copy number of 3p loss and 5q and 7q gain compared with normal tissues. We integrated RNA-seq and WGBS data to reveal methylation candidate genes associated with VHL disease-associated ccRCC; our results showed 124 hypermethylated and downregulated genes, and 245 hypomethylated and upregulated genes. By comparing the VHL disease-associated ccRCC transcriptome data with the sporadic ccRCC transcriptome data from the TCGA public database, we found that the major pathways of differential gene enrichment differed between them.Our study mapped the multiomics of copy number variation, methylation and mRNA level changes in tumor and normal tissues of clear cell renal cell carcinoma with VHL syndrome, which provides a solid foundation for the mechanistic study, biomarker screening, and therapeutic target discovery of clear cell renal cell carcinoma.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.