GATA5 CpG island methylation in renal cell cancer: a potential biomarker for metastasis and disease progression

OBJECTIVE To investigate whether GATA5 CpG island (CGI) methylation occurs in renal cell carcinoma (RCC) and is associated with clinical, histopathological characteristics or progression-free survival of patients. PATIENTS AND METHODS Methylation was quantified in 117 RCC samples and 89 paired adjacent normal tissues using quantitative combined bisulphite restriction analysis (COBRA). COBRA was evaluated in advance by pyrosequencing analyses of control RCC cell lines (coefficient of correlation, R = 0.95). Statistical analyses were carried out using the paired t-test for matched tumour tissue (TU) and adjacent normal tissue (adN) samples, logistic regression for comparisons of independent sample groups and Cox regression for analysis of progression-free survival. RESULTS In the present study, we found a significant higher mean relative methylation in TU (20.4%) than in adN (7.9%, P < 0.001) in paired samples of all RCCs. Increased GATA5 methylation in tumours was associated with metastasis (P = 0.005) and decreased progression-free survival (P = 0.005, HR = 4.59) in the clear-cell RCC (ccRCC) group. CGI methylation in advanced ccRCCs (pT >= 3 and/or N1, M1 or G2-3/G3) exceeds those detected in localized tumours (pT <= 2, N0, M0, G1/G1-2) (27.8% vs 11.0%, P < 0.001). CONCLUSIONS The association of GATA5 hypermethylation with metastasis and progression-free survival of patients indicates that epigenetic alterations of GATA5 participate in renal cell carcinogenesis. Moreover, GATA5 CGI methylation could serve as a biomarker for tumour progression, although prospective and functional investigations are necessary to clarify whether independent information for future clinical management of patients with RCC can be obtained.