BACKGROUND While a considerable number of tumor-specific hypermethylated loci have been identified in renal cell cancer (RCC), DNA methylation of loci showing successive increases in normal, tumoral, and metastatic tissues could point to genes with high relevance both for the process of tumor development and progression. Here, we report that DNA methylation of a locus in a genomic region corresponding to the 3'UTR of the transcription factor T-box brain 1 (TBR1) mRNA accumulates in normal renal tissues with age and possibly increased body mass index. Moreover, a further tissue-specific increase of methylation was observed for tumor and metastatic tissue samples. RESULTS Biometric analyses of the TCGA KIRC methylation data revealed candidate loci for age-dependent and tumor-specific DNA methylation within the last exon and in a genomic region corresponding to the 3'UTR TBR1 mRNA. To evaluate whether methylation of TBR1 shows association with RCC carcinogenesis, we measured 15 tumor cell lines and 907 renal tissue samples including 355 normal tissues, 175 tissue pairs of normal tumor adjacent and corresponding tumor tissue as well 202 metastatic tissues samples of lung, bone, and brain metastases by the use of pyrosequencing. Statistical evaluation demonstrated age-dependent methylation in normal tissue (R = 0.72, p < 2 × 10-16), association with adiposity (P = 0.019) and tumor-specific hypermethylation (P = 6.1 × 10-19) for RCC tissues. Comparison of tumor and metastatic tissues revealed higher methylation in renal cancer metastases (P = 2.65 × 10-6). CONCLUSIONS Our analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.

中文翻译：

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人肾组织中T盒脑1位点的与年龄，肿瘤和转移性组织相关的DNA超甲基化。

背景技术虽然在肾细胞癌（RCC）中已鉴定出大量的肿瘤特异性高甲基化基因座，但显示正常，肿瘤和转移性组织连续增加的基因座DNA甲基化可能指向与肿瘤过程都高度相关的基因发展和进步。在这里，我们报告基因组区域中对应于转录因子T-box脑1（TBR1）mRNA 3'UTR的基因组DNA甲基化会随着年龄的增长而在正常肾脏组织中积累，并可能增加体重指数。此外，观察到肿瘤和转移组织样品的甲基化进一步组织特异性增加。结果TCGA KIRC甲基化数据的生物特征分析显示，在最后一个外显子内和对应于3'UTR TBR1 mRNA的基因组区域中，年龄依赖性和肿瘤特异性DNA甲基化的候选基因座。为了评估TBR1的甲基化是否与RCC癌变相关，我们测量了15个肿瘤细胞系和907个肾脏组织样本，包括355个正常组织，175个正常肿瘤邻近组织和相应的肿瘤组织对以及202个肺，骨，焦磷酸测序法治疗人脑转移。统计评估表明，RCC组织在正常组织中年龄依赖性甲基化（R = 0.72，p <2×10-16），与肥胖相关（P = 0.019）和肿瘤特异性高甲基化（P = 6.1×10-19）。肿瘤和转移组织的比较显示，在肾癌转移中甲基化更高（P = 2.65×10-6）。结论我们的分析提供了TBR1甲基化与RCC发育和疾病进展之间的关联的统计证据。