Epigenetic inactivation of VGF associated with Urothelial Cell Carcinoma and its potential as a non-invasive biomarker using urine
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Masamichi Hayashi1,*, Heike Bernert1,2,*, Luciane Tsukamoto Kagohara1, Leonel Maldonado1,3, Mariana Brait1, Mark Schoenberg4, Trinity Bivalacqua4, George J Netto4,5,6, Wayne Koch1, David Sidransky1, Mohammad O. Hoque1,4,6
1 Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2 Department of Pathobiology, The University of Tennessee, The College of Veterinary Medicine, Knoxville, Tennessee, USA.
3 Department of Gynecology and Obstetrics-Gynecologic Specialties, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
4 Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
5 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
6 Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
* The Authors Contributed equally
Mohammad Obaidul Hoque, email:
Keywords: UCC, Epigenetics, Biomarker, Methylation
Received: February 28, 2014 Accepted: May 6, 2014 Published: May 7, 2014
Background: To identify new epigenetic markers and further characterize Urothelial Cell Carcinoma (UCC), we tested the promoter methylation (PM) status of 19 genes previously identified as cancer specific methylated genes in other solid tumors.
Methods: We used bisulfite sequencing, methylation specific PCR and quantitative methylation specific PCR (QMSP) to test the PM status of 19 genes in urothelial cancer cell lines.
Results: Among the 19 genes tested, VGF was found to be completely methylated in several UCC cell lines. VGF QMSP analysis showed that methylation values of almost all the primary 19 UCC tissues were higher than the paired normal tissues (P=0.009). In another cohort, 12/35 (34.3%) of low grade UCC cases displayed VGF methylation. As a biomarker for non-invasive detection of UCC, VGF showed a significantly higher frequency of methylation in urine from UCC cases (8/20) compared to controls (1/20) (P=0.020). After treatment of cell lines with 5-Aza-2’-deoxycytidine, VGF was robustly re-expressed. Forced expression of VGF in bladder cancer cell lines inhibited cell growth.
Conclusion: Selection of candidates from genome-wide screening approach in other solid tumors successfully identified UCC specific methylated genes.
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