Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis

Renal cell carcinoma (RCC) is among the ten most common malignancies. By far, the most common histology is clear cell (ccRCC). The Cancer Genome Atlas and other large scale sequencing studies of ccRCC have been integral to the current understanding of molecular events underlying RCC and its biology. However, these data sets have focused on primary RCC which often demonstrates indolent behavior. In contrast, metastatic disease is the major cause of mortality associated with ccRCC. However, data sets examining metastatic tumor are sparse. We therefore undertook an integrative analysis of gene expression and DNA methylome profiling of metastatic ccRCC in addition to primary RCC and normal kidney. Integrative analysis of the methylome and transcriptome identified over 30 RCC specific genes whose mRNA expression inversely correlated with promoter methylation including several known targets of hypoxia inducible factors (HIFs). Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation. Collectively, our data provide novel insight into biology of aggressive RCC. Furthermore, they demonstrate a clear role for epigenetics in the promotion of HIF signaling and invasive phenotypes in renal cancer. Refer to individual Series

肾细胞癌（Renal cell carcinoma, RCC）是十大常见恶性肿瘤之一，其中最常见的组织学亚型为透明细胞肾细胞癌（clear cell RCC, ccRCC）。癌症基因组图谱（The Cancer Genome Atlas）及其他针对透明细胞肾细胞癌的大规模测序研究，为当前学界阐明肾细胞癌发生的分子事件及其生物学特性提供了核心支撑。然而，此类数据集多聚焦于通常呈惰性生物学行为的原发性肾细胞癌。与之相对，转移性疾病是透明细胞肾细胞癌致死的主要原因，但目前针对转移性肾肿瘤的相关数据集仍十分匮乏。为此，本研究针对转移性透明细胞肾细胞癌、原发性肾细胞癌及正常肾脏组织，开展了基因表达与DNA甲基化组谱的整合分析。通过对甲基化组与转录组的整合分析，本研究共鉴定出30余种肾细胞癌特异性基因，其mRNA表达与启动子甲基化水平呈负相关，其中包含若干已知的缺氧诱导因子（hypoxia inducible factors, HIFs）靶基因。值得注意的是，多个编码代谢相关蛋白的基因被鉴定为经甲基化调控呈现差异表达。综上，本研究数据为侵袭性肾细胞癌的生物学特性提供了全新认知。此外，本研究明确了表观遗传在肾癌中促进缺氧诱导因子信号通路及侵袭表型形成中的关键作用。详见各数据集系列。