Hsa-mir-124-3 CpG island methylation is associated with advanced tumours and disease recurrence of patients with clear cell renal cell carcinoma

Abstract

Background:Whether methylation of the microRNA (mir)-124-3 CpG island is of relevance for the clinical course of a solid cancer and whether it shows association with clinicopathology or survival of patients with renal cell cancer (RCC) is not known as yet.Methods:In a cross-sectional study, relative methylation of mir-124-3 was measured in 111 RCC samples and 77 paired normal appearing tissues using quantitative methyl-specific PCR. Results were statistically compared with tumour histology, clinicopathological parameters and disease recurrence.Results:We found tumour-specific hypermethylation of mir-124-3 in samples of RCCs with clear cell histology (ccRCC) compared with paired normal appearing tissues (P<0.0001). Methylation was significantly increased in tumours with state of advanced disease (P<0.0001). Higher relative methylation was associated with worse recurrence-free survival in both univariate (hazard ratio=9.37; P=0.0005) as well as bivariate Cox regression analyses considering age, sex, diameter of tumours and state of advanced disease, metastasis and lymph node metastases as covariates (hazard ratios=5.9–18.2; P-values of 0.0003–0.008).Conclusion:We identified mir-124-3 CpG islands (CGI) methylation as a relevant epigenetic mark for ccRCC thus underlining the need for functional studies of potentially affected signalling pathways in kidney tumour models. Methylation of mir-124-3 is suggested as an independent prognosticator for ccRCC.

The epigenetic landscape of renal cancer

“…As with other tumour suppressors genes, individual mi RNAs are often silenced or downregulated in RCC by promoter methylation 4,[210][211][212] and have single nucleotide polymorphisms (SNPs). These SNPs alter the ability of mi RNAs to bind to target sequences and are associated with RCC susceptibility 213,214 .…”

Relationship Between Noncoding RNA Dysregulation and Epigenetic Mechanisms in Cancer

“…A more comprehensive analysis of epigenetically silenced miRNA genes in ALL has identifi ed methylation of 13 miRNA genes (miR-9-1, miR-9-2, miR-9-3, miR-10b, miR-34b, miR-34c, miR124-1, miR-124-2, miR-124-3, miR-132, miR-212, miR-196b, and miR-203), and ALLs with at least one methylated miRNA gene show signifi cantly poorer disease-free and overall survival than the unmethylated group [ 19 ]. Similarly, methylation of miR-9-3, miR-124-2, and miR124-3 is associated with larger tumor size and poorer progression-free survival in NSCLC [ 7 ], and methylation of miR-124-3 is associated with disease recurrence in clear cell renal carcinoma [ 123 ]. Methylation of miR-34b/c is also associated with a high probability of recurrence and poor overall survival in NSCLC [ 22 ].…”

Decreased mRNA expression of GATA1 and GATA2 is associated with tumor aggressiveness and poor outcome in clear cell renal cell carcinoma

“…The local ethic committees of Hannover Medical School and Eberhard Karls University of Tuebingen approved sample collection and study design, a general written consent was obtained. TNM classification and histological grading (G) was done according to the Union for Cancer Control 2002 and Thoenes et al [18] as described previously [19]. RCC tissues were obtained from open or laparoscopic nephrectomies or partial resections.…”