Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples

Clin Cancer Res. 2010 Dec 1;16(23):5842-51. doi: 10.1158/1078-0432.CCR-10-1312. Epub 2010 Oct 25.

Abstract

Purpose: To identify a panel of epigenetic biomarkers for accurate bladder cancer (BlCa) detection in urine sediments.

Experimental design: Gene expression microarray analysis of BlCa cell lines treated with 5-aza-2'-deoxycytidine and trichostatin A as well as 26 tissue samples was used to identify a list of novel methylation candidates for BlCa. Methylation levels of candidate genes were quantified in 4 BlCa cell lines, 50 BlCa tissues, 20 normal bladder mucosas (NBM), and urine sediments from 51 BlCa patients and 20 healthy donors, 19 renal cancer patients, and 20 prostate cancer patients. Receiver operator characteristic curve analysis was used to assess the diagnostic performance of the gene panel.

Results: GDF15, HSPA2, TMEFF2, and VIM were identified as epigenetic biomarkers for BlCa. The methylation levels were significantly higher in BlCa tissues than in NBM (P < 0.001) and the cancer specificity was retained in urine sediments (P < 0.001). A methylation panel comprising GDF15, TMEFF2, and VIM correctly identified BlCa tissues with 100% sensitivity and specificity. In urine samples, the panel achieved a sensitivity of 94% and specificity of 100% and an area under the curve of 0.975. The gene panel could discriminate BlCa from both healthy individuals and renal or prostate cancer patients (sensitivity, 94%; specificity, 90%).

Conclusions: By using a genome-wide approach, we have identified a biomarker panel that allows for early and accurate noninvasive detection of BlCa using urine samples.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / genetics*
  • Carcinoma / diagnosis*
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / urine
  • Case-Control Studies
  • Cell Line, Tumor
  • DNA, Neoplasm / analysis
  • DNA, Neoplasm / urine
  • Early Detection of Cancer / methods
  • Epigenesis, Genetic / genetics*
  • Gene Expression Profiling
  • Growth Differentiation Factor 15 / genetics*
  • Growth Differentiation Factor 15 / metabolism
  • Growth Differentiation Factor 15 / physiology
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology
  • Microarray Analysis
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology
  • Prognosis
  • Reproducibility of Results
  • Urinalysis / methods
  • Urinary Bladder Neoplasms / diagnosis*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / urine
  • Vimentin / genetics*
  • Vimentin / metabolism
  • Vimentin / physiology

Substances

  • Biomarkers, Tumor
  • DNA, Neoplasm
  • Growth Differentiation Factor 15
  • Membrane Proteins
  • Neoplasm Proteins
  • TMEFF2 protein, human
  • Vimentin