title: 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.
abstract: By a candidate gene approach, we analyzed the promoter methylation (PM) of 8 genes genes (ARF, TIMP3, RAR-β2, NID2, CCNA1, AIM1, CALCA and CCND2) by quantitative methylation specific PCR (QMSP) in 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%), 50/73 (68%) and 94/148 (63.5%) respectively] than controls [0/56 (0%), 10/60 (17%) and 16/56 (28.5%), respectively)]. Most importantly we found any one of the 3 markers methylation 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.
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. These authors contributed equally to this work.
authors: Leonel
authors: L
authors: Maldonado
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. These authors contributed equally to this work.
authors: Mariana
authors: M
authors: Brait
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Christina
authors: C
authors: Michailidi
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Enrico
authors: E
authors: Munari
authors: Department of Urology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Tina
authors: T
authors: Driscoll
authors: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Luciana
authors: L
authors: Schultz
authors: Department of Urology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Trinity
authors: T
authors: Bivalacqua
authors: Department of Urology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Mark
authors: M
authors: Schoenberg
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors: David
authors: D
authors: Sidransky
authors: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA. Department of Urology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: George J
authors: GJ
authors: Netto
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Department of Urology, Johns Hopkins University, Baltimore, Maryland, USA. Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Mohammad Obaidul
authors: MO
authors: Hoque
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D056750:Cyclin A1 / Q000235:genetics; D056742:Cyclin D2 / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000652:urine*; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000601:surgery / Q000652:urine*
chemical_list: D014408:Biomarkers, Tumor; C503745:CCNA1 protein, human; C080336:CCND2 protein, human; D056750:Cyclin A1; D056742:Cyclin D2; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine