Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples.
OBJECTIVE
To identify a panel of epigenetic biomarkers for accurate bladder cancer (BlCa) detection in urine sediments.


METHODS
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.
Costa
Vera L
VL
Cancer Epigenetics Group, Portuguese Oncology Institute - Porto, Porto, Portugal.
Henrique
Rui
R
Danielsen
Stine A
SA
Duarte-Pereira
Sara
S
Eknaes
Mette
M
Skotheim
Rolf I
RI
Rodrigues
Angelo
A
Magalhães
José S
JS
Oliveira
Jorge
J
Lothe
Ragnhild A
RA
Teixeira
Manuel R
MR
Jerónimo
Carmen
C
Lind
Guro E
GE
D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000652:urine; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000032:analysis / Q000652:urine; D055088:Early Detection of Cancer / Q000379:methods; D044127:Epigenesis, Genetic / Q000235:genetics*; D020869:Gene Expression Profiling; D055436:Growth Differentiation Factor 15 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D046228:Microarray Analysis; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011379:Prognosis; D015203:Reproducibility of Results; D016482:Urinalysis / Q000379:methods; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D014746:Vimentin / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D055436:Growth Differentiation Factor 15; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C423567:TMEFF2 protein, human; D014746:Vimentin