title: Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma.
abstract: The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete.Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma).A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival.Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.
authors.affiliation: Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Federico Pio
authors.initials: FP
authors.lastname: Fabrizio
authors.affiliation: Genetic and Clinic Pathology Unit, University Campus Bio-Medico of Rome, Rome, Italy.|Department of Urology, Regina Elena National Cancer Institute, Rome, Italy.|Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Costantini
authors.affiliation: Unit of Biostatistics, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.affiliation: Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: la Torre
authors.affiliation: Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Sparaneo
authors.affiliation: Unit of Biostatistics, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Department of Bioscience, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Poeta
authors.affiliation: Department of Urology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Gallucci
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Steno
authors.initials: S
authors.lastname: Sentinelli
authors.affiliation: Unit of Pathology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Graziano
authors.affiliation: Unit of Pathology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Parente
authors.affiliation: Department of Urology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pompeo
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: De Salvo
authors.affiliation: Department of Urology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Simone
authors.affiliation: Department of Urology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Papalia
authors.affiliation: Genetic and Clinic Pathology Unit, University Campus Bio-Medico of Rome, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Picardo
authors.affiliation: Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Balsamo
authors.affiliation: UOC of Urology, Campus Bio-Medico University Hospital, Rome, Italy.
authors.forename: Gerardo Paolo
authors.initials: GP
authors.lastname: Flammia
authors.affiliation: Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Trombetta
authors.affiliation: Genetic and Clinic Pathology Unit, University Campus Bio-Medico of Rome, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pantalone
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: Kok
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Ferronika
authors.initials: F
authors.lastname: Paranita
authors.affiliation: Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.
authors.forename: Lucia Anna
authors.initials: LA
authors.lastname: Muscarella
authors.affiliation: Laboratory of Oncology, IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy.|Genetic and Clinic Pathology Unit, University Campus Bio-Medico of Rome, Rome, Italy.
authors.forename: Vito Michele
authors.initials: VM
authors.lastname: Fazio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis
chemical_list: D004791:Enzyme Inhibitors; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D001374:Azacitidine
keywords: KEAP1; ccRCC; epigenetic biomarker; methylation; outcome