Clinical Research Papers:
An epigenetic marker panel for recurrence risk prediction of low grade papillary urothelial cell carcinoma (LGPUCC) and its potential use for surveillance after transurethral resection using urine
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Leonel Maldonado1,5,*, Mariana Brait1,*, Christina Michailidi1, Enrico Munari1,2, Tina Driscoll3, Luciana Schultz2, Trinity Bivalacqua3, Mark Schoenberg3, David Sidransky1, George J. Netto2,3 and Mohammad Obaidul Hoque1,3,4
1 Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
2 Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
3 Department of Urology, Johns Hopkins University, Baltimore, Maryland, USA
4 Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA
5 Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
* These authors contributed equally to this work
Mohammad Obaidul Hoque, email:
George J Netto, email:
Keywords: LGPUCC, Recurrence, Epigenetics, Biomarkers, DNA methylation
Received: January 21, 2014 Accepted: June 22, 2014 Published: June 23, 2014
By a candidate gene approach, we analyzed the promoter methylation (PM) of 8 genes (ARF, TIMP3, RAR-β2, NID2, CCNA1, AIM1, CALCA and CCND2) by quantitative methylation specific PCR (QMSP) in the DNA of 17 non-recurrent and 19 recurrent noninvasive low grade papillary urothelial cell carcinoma (LGPUCC) archival tissues. Among the genes tested, by establishing an empiric cutoff value, CCND2, CCNA1, NID2, and CALCA showed higher frequency of methylation in recurrent than in non-recurrent LGPUCC: CCND2 10/19 (53%) vs. 2/17 (12%) (p=0.014); CCNA1 11/19 (58%) vs. 4/17 (23.5%) (p=0.048); NID2 13/19 (68%) vs. 3/17 (18%) (p=0.003) and CALCA 10/19 (53%) vs. 4/17 (23.5%) (p=0.097), respectively. We further analyzed PM of CCND2, CCNA1, and CALCA in urine DNA from UCC patients including LGPUCC and controls. The frequency of CCND2, CCNA1, and CALCA was significantly higher (p<0.0001) in urine of UCC cases [38/148 (26%), 50/635%) respectively] than controls [0/56 (0%), 10/60 (17%) and 16/56 (28.5%), respectively)]. Most importantly we found at least one of the 3 markers were methylated positive in 25 out of 30 (83%) cytology negative LGPUCC cases. We also explored the biological function of CCNA1 in UCC. Prospective confirmatory studies are needed to develop a reliable tool for prediction of recurrence using primary LGPUCC tissues and/or urine.
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