Methylation of the TPEF- and PAX6-promoters is increased in early bladder cancer and in normal mucosa adjacent to pTa tumours.
OBJECTIVE
To evaluate CpG island methylation patterns of cancer-associated genes for their applicability as molecular biomarkers for the detection of superficial bladder cancer and for the discrimination of invasive from noninvasive tumours.


METHODS
We analysed the methylation status of CpG islands in the promoter region of the cancer-associated genes GSTP1, DAPK, MDR1, TPEF, PAX6, and TSLC1 in primary papillary bladder cancer specimens from 39 patients (pT1 10, pTis one, pTa 20, pT2 five). Tumour-adjacent normal mucosa served as the control. The DNAs were bisulphite-treated and submitted to methylation-specific real-time polymerase chain reactions.


RESULTS
Only TPEF and PAX6 had substantial CpG island methylation percentages. The TPEF- and PAX6-promoters also had significantly higher methylation rates in tumour tissue compared with the normal tumour-adjacent tissue. Interestingly, the methylation rates of the TPEF- and the PAX6-promoter were higher in adjacent normal tissues from bladders with pTa then in those with pT1 tumours.


CONCLUSIONS
Our results shed a critical light on the hypothesis that CpG island hypermethylation of the GSTP1-, DAPK-, MDR1- and TSLC1-promoter could represent molecular biomarkers for bladder cancer diagnosis and detection. However, methylated PAX6- or TPEF-promoters could represent biomarkers for this disease. Additional studies are needed to evaluate whether methylation rates of these genes in normal bladder tissues are applicable as accessory markers for the tumour state or its invasive behaviour.
Hellwinkel
Olaf J C
OJ
Martini Prostate Cancer Center, Department of Urology, University Hospital Eppendorf, Hamburg, Germany. hellwinkel@uke.uni-hamburg.de
Kedia
Merab
M
Isbarn
Hendrik
H
Budäus
Lars
L
Friedrich
Martin G
MG
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics
D005136:Eye Proteins; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; C423567:TMEFF2 protein, human