Klinik für Urologie und urologische Onkologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625, Hannover, Germany.
Brandenburgisches Landesinstitut für Rechtsmedizin, Lindstedter Chaussee 6, D-14469, Potsdam, Germany.
Clin Epigenetics. 2020 Feb 18;12(1):33. doi: 10.1186/s13148-020-0823-x.
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.
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), association with adiposity (P = 0.019) and tumor-specific hypermethylation (P = 6.1 × 10) for RCC tissues. Comparison of tumor and metastatic tissues revealed higher methylation in renal cancer metastases (P = 2.65 × 10).
Our analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.
虽然已经在肾细胞癌 (RCC) 中鉴定出相当数量的肿瘤特异性高甲基化基因座，但在正常、肿瘤和转移组织中显示连续增加的基因座的 DNA 甲基化可能指向与肿瘤发生和进展过程高度相关的基因。在这里，我们报告转录因子 T 盒脑 1 (TBR1) mRNA 3'UTR 相应基因组区域中一个基因座的 DNA 甲基化随年龄和可能增加的体重指数而在正常肾组织中累积。此外，在肿瘤和转移组织样本中观察到进一步的组织特异性甲基化增加。
TCGA KIRC 甲基化数据的生物统计学分析显示候选基因座，用于年龄依赖性和肿瘤特异性 DNA 甲基化，位于最后外显子和对应于 TBR1 mRNA 3'UTR 的基因组区域。为了评估 TBR1 的甲基化是否与 RCC 癌变有关，我们使用焦磷酸测序测量了 15 个肿瘤细胞系和 907 个肾组织样本，包括 355 个正常组织、175 对正常肿瘤相邻和相应肿瘤组织以及 202 个来自肺、骨和脑转移的转移组织样本。统计评估表明，正常组织中存在年龄依赖性甲基化（R = 0.72，p < 2 × 10），与肥胖（P = 0.019）和 RCC 组织的肿瘤特异性高甲基化（P = 6.1 × 10）相关。对肿瘤和转移组织的比较表明，肾癌细胞转移中甲基化程度更高（P = 2.65 × 10）。
我们的分析提供了 TBR1 甲基化与 RCC 发展和疾病进展之间关联的统计证据。
