Abstract
BackgroundWhile 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.ResultsBiometric 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).ConclusionsOur analyses provide statistical evidence of association between methylation of TBR1 and RCC development and disease progression.
Highlights
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
Biometrical analysis of genome-wide data such as from the The Cancer Genome Atlas network (TCGA) kidney renal clear cell carcinoma (KIRC) study providing methylation information for approx. 435,000 loci in clear cell variant of RCC (ccRCC) and normal kidney tissues substantially improves the efficacy of the search for new epigenetic candidate markers of potential use for the clinical management of ccRCC
Among the top 50 CpG sites identified as candidates for age-related methylation in the genome-wide biometric analysis, we identified four CpG loci annotating either to the last exon or the genomic region corresponding to the 3′UTR of the T-box brain 1 (TBR1) mRNA (Fig. 1): cg05301866, cg12757011, cg06942701, and cg06488443
Summary
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. Serth et al Clinical Epigenetics (2020) 12:33 before as well as the KIRC study itself showed that DNA methylation occur with high frequency in RCC. DNA methylation in normal kidney tissues has been found often to be associated with age and other epidemiologic risk factors [8,9,10] as well as renal cell cancer risk [11]. The search for new epigenetic marks such as DNA methylation associating with crucial steps of carcinogenesis may provide a rationale for the development of useful clinical biomarkers, starting points for subsequent targeted functional analyses as well as epigenetic-based therapies [20]. Biometrical analysis of genome-wide data such as from the TCGA KIRC study providing methylation information for approx. 435,000 loci in ccRCC and normal kidney tissues substantially improves the efficacy of the search for new epigenetic candidate markers of potential use for the clinical management of ccRCC
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