Cancer Research UK Renal Molecular Oncology Group, University of Birmingham, Birmingham, UK.
Oncogene. 2011 Mar 24;30(12):1390-401. doi: 10.1038/onc.2010.525. Epub 2010 Dec 6.
The detection of promoter region hypermethylation and transcriptional silencing has facilitated the identification of candidate renal cell carcinoma (RCC) tumour suppressor genes (TSGs). We have used a genome-wide strategy (methylated DNA immunoprecipitation (MeDIP) and whole-genome array analysis in combination with high-density expression array analysis) to identify genes that are frequently methylated and silenced in RCC. MeDIP analysis on 9 RCC tumours and 3 non-malignant normal kidney tissue samples was performed, and an initial shortlist of 56 candidate genes that were methylated by array analysis was further investigated; 9 genes were confirmed to show frequent promoter region methylation in primary RCC tumour samples (KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse (P=0.0046). The identification of candidate epigenetically inactivated RCC TSGs provides new insights into renal tumourigenesis.
启动子区域超甲基化和转录沉默的检测促进了候选肾细胞癌 (RCC) 肿瘤抑制基因 (TSG) 的鉴定。我们使用全基因组策略（甲基化 DNA 免疫沉淀 (MeDIP) 和全基因组芯片分析结合高密度表达芯片分析）来鉴定在 RCC 中经常甲基化和沉默的基因。对 9 个 RCC 肿瘤和 3 个非恶性正常肾组织样本进行了 MeDIP 分析，并对通过芯片分析甲基化的 56 个候选基因的初始短名单进行了进一步研究；9 个基因在原发性 RCC 肿瘤样本中频繁显示启动子区域甲基化（KLHL35（39%）、QPCT（19%）、SCUBE3（19%）、ZSCAN18（32%）、CCDC8（35%）、FBN2（34%）、ATP5G2（36%）、PCDH8（58%）和 CORO6（22%））。KLHL35、QPCT、SCUBE3、ZSCAN18、CCDC8 和 FBN2 的 RNAi 敲低导致了无锚定依赖性生长优势。SCUBE3 的肿瘤甲基化与癌症死亡或复发的风险显著增加相关（P=0.0046）。候选表观遗传失活的 RCC TSG 的鉴定为肾肿瘤发生提供了新的见解。
