PURPOSE: Polyamines are important regulators of cell growth and death. The polyamine modulated factor-1 (PMF-1) is involved in polyamine homeostasis. After identifying an enriched CpG island encompassing the PMF1 promoter, we aimed at evaluating the clinical relevance of PMF1 methylation in bladder cancer. EXPERIMENTAL DESIGN: The epigenetic silencing of PMF1 by hypermethylation was tested in bladder cancer cells (n = 11) after azacytidine treatment. PMF1 methylation status was evaluated in 507 bladder tumors and 118 urinary specimens of bladder cancer patients and controls. PMF1 protein expression was analyzed by immunohistochemistry on tissue arrays containing bladder tumors for which PMF1 methylation was assessed (n = 218). RESULTS: PMF1 hypermethylation was associated with gene expression loss, being restored in vitro by a demethylating agent. An initial set of 101 primary frozen bladder tumors served to identify PMF1 hypermethylation in 88.1% of the cases. An independent set of 406 paraffin-embedded tumors also revealed a high PMF1 methylation rate (77.6%). PMF1 methylation was significantly associated with increasing stage (P = 0.025). Immunohistochemical analyses revealed that PMF1 methylation was associated with cytoplasmic PMF1 expression loss (P = 0.032). PMF1 protein expression patterns were significantly associated with stage (P < 0.001), grade (P < 0.001), and poor overall survival using univariate (P < 0.001) and multivariate (P = 0.011) analyses. Moreover, PMF1 methylation in urinary specimens distinguished bladder cancer patients from controls (area under the curve = 0.800). CONCLUSION: PMF1 was identified to be epigenetically modified in bladder cancer. The association of PMF1 methylation with tumor progression and its diagnostic ability using urinary specimens support including PMF1 assessment for the clinical management of bladder cancer patients.
PURPOSE:Polyamines are important regulators of cell growth and death. The polyamine modulated factor-1 (PMF-1) is involved in polyamine homeostasis. After identifying an enriched CpG island encompassing the PMF1 promoter, we aimed at evaluating the clinical relevance of PMF1 methylation in bladder cancer. EXPERIMENTAL DESIGN: The epigenetic silencing of PMF1 by hypermethylation was tested in bladder cancer cells (n = 11) after azacytidine treatment. PMF1 methylation status was evaluated in 507 bladder tumors and 118 urinary specimens of bladder cancerpatients and controls. PMF1 protein expression was analyzed by immunohistochemistry on tissue arrays containing bladder tumors for which PMF1 methylation was assessed (n = 218). RESULTS:PMF1 hypermethylation was associated with gene expression loss, being restored in vitro by a demethylating agent. An initial set of 101 primary frozen bladder tumors served to identify PMF1 hypermethylation in 88.1% of the cases. An independent set of 406 paraffin-embedded tumors also revealed a high PMF1 methylation rate (77.6%). PMF1 methylation was significantly associated with increasing stage (P = 0.025). Immunohistochemical analyses revealed that PMF1 methylation was associated with cytoplasmic PMF1 expression loss (P = 0.032). PMF1 protein expression patterns were significantly associated with stage (P < 0.001), grade (P < 0.001), and poor overall survival using univariate (P < 0.001) and multivariate (P = 0.011) analyses. Moreover, PMF1 methylation in urinary specimens distinguished bladder cancerpatients from controls (area under the curve = 0.800). CONCLUSION:PMF1 was identified to be epigenetically modified in bladder cancer. The association of PMF1 methylation with tumor progression and its diagnostic ability using urinary specimens support including PMF1 assessment for the clinical management of bladder cancerpatients.
Authors: Carmen J Marsit; E Andres Houseman; Brock C Christensen; Luc Gagne; Margaret R Wrensch; Heather H Nelson; Joseph Wiemels; Shichun Zheng; John K Wiencke; Angeline S Andrew; Alan R Schned; Margaret R Karagas; Karl T Kelsey Journal: PLoS One Date: 2010-08-23 Impact factor: 3.240
Authors: Benjamin F J Verhaaren; Stéphanie Debette; Joshua C Bis; Jennifer A Smith; M Kamran Ikram; Hieab H Adams; Ashley H Beecham; Kumar B Rajan; Lorna M Lopez; Sandra Barral; Mark A van Buchem; Jeroen van der Grond; Albert V Smith; Katrin Hegenscheid; Neelum T Aggarwal; Mariza de Andrade; Elizabeth J Atkinson; Marian Beekman; Alexa S Beiser; Susan H Blanton; Eric Boerwinkle; Adam M Brickman; R Nick Bryan; Ganesh Chauhan; Christopher P L H Chen; Vincent Chouraki; Anton J M de Craen; Fabrice Crivello; Ian J Deary; Joris Deelen; Philip L De Jager; Carole Dufouil; Mitchell S V Elkind; Denis A Evans; Paul Freudenberger; Rebecca F Gottesman; Vilmundur Guðnason; Mohamad Habes; Susan R Heckbert; Gerardo Heiss; Saima Hilal; Edith Hofer; Albert Hofman; Carla A Ibrahim-Verbaas; David S Knopman; Cora E Lewis; Jiemin Liao; David C M Liewald; Michelle Luciano; Aad van der Lugt; Oliver O Martinez; Richard Mayeux; Bernard Mazoyer; Mike Nalls; Matthias Nauck; Wiro J Niessen; Ben A Oostra; Bruce M Psaty; Kenneth M Rice; Jerome I Rotter; Bettina von Sarnowski; Helena Schmidt; Pamela J Schreiner; Maaike Schuur; Stephen S Sidney; Sigurdur Sigurdsson; P Eline Slagboom; David J M Stott; John C van Swieten; Alexander Teumer; Anna Maria Töglhofer; Matthew Traylor; Stella Trompet; Stephen T Turner; Christophe Tzourio; Hae-Won Uh; André G Uitterlinden; Meike W Vernooij; Jing J Wang; Tien Y Wong; Joanna M Wardlaw; B Gwen Windham; Katharina Wittfeld; Christiane Wolf; Clinton B Wright; Qiong Yang; Wei Zhao; Alex Zijdenbos; J Wouter Jukema; Ralph L Sacco; Sharon L R Kardia; Philippe Amouyel; Thomas H Mosley; W T Longstreth; Charles C DeCarli; Cornelia M van Duijn; Reinhold Schmidt; Lenore J Launer; Hans J Grabe; Sudha S Seshadri; M Arfan Ikram; Myriam Fornage Journal: Circ Cardiovasc Genet Date: 2015-02-07