title: GATA5 CpG island methylation in renal cell cancer: a potential biomarker for metastasis and disease progression.
abstract: GATA5 CpG island (CGI) methylation and transcriptional inactivation is involved in colorectal and gastric cancer. Whether DNA methylation of GATA5 affects clinical pathology is still unclear. In the present study, we analysed, for the first time, CGI methylation in RCC and its association with clinicopathological parameters and progression-free survival of patients. We show for the first time GATA5 CGI hypermethylation in RCC. Moreover, we found out that increased methylation is statistically associated with status of metastasis, progressive disease and shortened progression-free survival. The present study underline the necessity for further functional investigations as well as prospective survival analyses to clarify whether GATA5 promoter methylation can provide independent information for future clinical management of patients with RCC.
  
  
  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.
  
  
  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.
authors.affiliation: Department of Urology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Peters
authors.forename: Hendrik
authors.initials: H
authors.lastname: Eggers
authors.forename: Faranaz
authors.initials: F
authors.lastname: Atschekzei
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.forename: Sandra
authors.initials: S
authors.lastname: Waalkes
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Tränkenschuh
authors.forename: Anika
authors.initials: A
authors.lastname: Grosshennig
authors.forename: Axel S
authors.initials: AS
authors.lastname: Merseburger
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.forename: Markus A
authors.initials: MA
authors.lastname: Kuczyk
authors.forename: Jürgen
authors.initials: J
authors.lastname: Serth
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D050992:GATA5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human