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DNA methylation profile of cancerous and non-cancerous renal tissues

ABSTRACT: Renal cell carcinoma (RCC), particularly clear cell RCC (ccRCC), is the most common type of kidney tumors characterized by the highest mortality rate of the genitourinary cancers. Lack of symptoms leads to late detection of the disease using conventional imagining procedures. There is an urgent need for new diagnostic biomarkers with the potential for early detection and prediction of high risk of progression. In the present study, based on microarray profiling of DNA methylation in 11 pairs of ccRCC and noncancerous renal tissues (NRT), the methylation at regulatory regions of six putative ccRCC biomarkers was further analyzed in 123 ccRCC and 45 NRT samples by means of methylation specific PCR (MSP). Thereafter, the quantitative MSP was applied for the methylation analysis in the urine samples of 123 ccRCC patients and 93 asymptomatic controls (ASC). The comparison of ccRCC and NRT samples revealed significant methylation differences in 1319 genes, of which 191 were hypermethylated and 1128 were hypomethylated. DNA methylation of selected genes were validated by means of MSP and significantly higher methylation frequencies for all genes was found in ccRCC tissues compared to NRT (33-60% vs. 0-11%). Methylated status of at least one gene was significantly related with various adverse clinical-pathological parameters of the patients, including larger tumor size, higher tumor pathological stage, grade, intravascular and fat invasion as welll as tumor necrosis. The multivariate Cox regression model revealed the methylation in a panel of selected three genes as independent prognostic biomarker of ccRCC. Moreover, five genes were characterised by higher methylation intensity in the urine samples of ccRCC patients, as compared to ASC, and various combination of these biomarkers revealed moderate-to-high sensitivity and specificity values for the diagnosis of ccRCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166734 | GEO | 2021/02/15

REPOSITORIES: GEO

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Project description:Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Currently, there are no biomarkers for the diagnostic, prognostic, or predictive applications in RCC. MicroRNAs (miRNAs) are short non protein-coding RNAs that negatively regulate gene expression and have been shown to be involved in cancer. We analyzed a total of 70 matched pairs of clear cell RCC (ccRCC) and normal kidney tissues from the same patients by microarray analysis and validated our results by quantitative real time PCR. We identified 166 miRNAs significantly dysregulated in ccRCC. MiR-122, miR-155 and miR-210 had the highest fold changes of overexpression while miR-200c, miR-335, and miR-218 were the most downregulated. We performed extensive bioinformatics analysis including a combinatorial analysis of previously reported miRNAs dysregulated in RCC and extensive target prediction analysis. Many miRNAs were predicted to target a number of genes involved in RCC pathogenesis. Our results showed that miRNA dysregulation in RCC can be attributed in part, to chromosomal aberrations, the co-regulation of miRNA clusters, and co-expression with host genes. We also correlated miRNA expression with clinical characteristics and found miR-155 expression was correlated with ccRCC tumor size. In conclusion, our analysis showed that a number of miRNAs are dysregulated in ccRCC and may contribute to kidney cancer pathogenesis by targeting more than one key molecule. We identified mechanisms that may contribute to miRNA dysregulation in ccRCC. Dysregulated miRNAs represent potential biomarkers for kidney cancer. We preformed a miRNA microarray on 20 pairs of matched primary clear cell renal cell carcinoma (ccRCC) and normal kidney tissue from the same patient (St. Michael's Hospital, Toronto, Canada). One matched pair was used per array for a total of 20 arrays. Microarray results were validated by quantitative real time PCR using an independent set of 50 matched pairs of ccRCC and normal kidney tissue from the same patient.

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DNA methylation profile of cancerous and non-cancerous renal tissues

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