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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.

Age-, tumor-, and metastatic tissue-associated DNA hypermethylation of a T-box brain 1 locus in human kidney tissue