Remodeling of major genomic fabrics and their interplay in metastatic clear cell renal carcinoma. Homo sapiens

Clear cell renal carcinoma (CCRC) accounts for >80% of all kidney cancers but what triggers the tumorigenesis in the kidney and metastases in the bones are still under debate. Our hypothesis is that remodeling of the genomic fabrics of certain functional pathways and their interplay beyond critical limits are key causes of CCRC. We profiled the transcriptomes of metastatic chest wall and of two primary cancerous sites of the renal medulla and compared them with that of non-cancerous kidney resection margins. Samples were collected from a 74 years old male with metastatic carcinoma, consistent with renal cell carcinoma, clear cell type, Fuhrman grade 3, who undergone total right kidney nephrectomy and resection of a chest wall mass. Transcriptomic analysis pointed the tumor region in the right kidney that led to the chest wall metastases. The tumor proved heterogeneous not only in the expression level but also in the expression control, coordination and interplay of pathways responsible for cellular processes and genetic and environmental information processing. The differently regulated pathways in the two sides of the tumor: CCRC, and HIF-1, Vegfa and mTor signaling indicate activation of distinct mechanisms. Overall design: Four-conditions (CTR = control - non-cancerous kidney resection margins, PTA = primary tumor side A, PTB = primary tumor side B, MET = chest wall metastasis. Four biological replicates of each condition.

透明细胞肾细胞癌（Clear cell renal carcinoma, CCRC）占所有肾脏恶性肿瘤的80%以上，但目前对于触发肾脏肿瘤发生及骨转移的具体机制仍存在争议。本研究提出假说：特定功能通路的基因组构象重塑及其相互作用突破临界阈值，是透明细胞肾细胞癌发生的核心诱因。我们对转移性胸壁组织以及肾髓质的两处原发肿瘤位点的转录组进行了谱分析，并将其与非癌性肾切除切缘组织的转录组进行对照。样本采集自一名74岁男性转移性癌患者，该患者经确诊为透明细胞型肾细胞癌，Fuhrman分级3级（Fuhrman grade 3），曾接受右肾全切除术及胸壁肿块切除术。转录组分析定位出了右肾中引发胸壁转移的肿瘤区域。该肿瘤不仅在基因表达水平上存在异质性，在调控细胞过程、遗传与环境信息处理的通路的表达调控、协同作用及相互关联层面同样呈现异质性。肿瘤两侧存在差异调控的通路：透明细胞肾细胞癌相关通路、缺氧诱导因子1（HIF-1）、血管内皮生长因子A（Vegfa）以及哺乳动物雷帕霉素靶蛋白（mTor）信号通路，提示存在不同的激活机制。实验整体设计：共设置四组实验条件（CTR=对照组——非癌性肾切除切缘组织；PTA=原发肿瘤A侧；PTB=原发肿瘤B侧；MET=胸壁转移灶），每组设置4个生物学重复。