title: A Four-Gene Promoter Methylation Marker Panel Consisting ofGREM1, NEURL, LAD1,andNEFHPredicts Survival of Clear Cell Renal Cell Cancer Patients.
abstract: Purpose:The currently used prognostic models for patients with nonmetastatic clear cell renal cell carcinoma (ccRCC) are based on clinicopathologic features and might be improved by adding molecular markers. Epigenetic alterations occur frequently in ccRCC and are promising biomarkers. The aim of this study is to identify prognostic promoter methylation markers for ccRCC.Experimental Design:We integrated data generated by massive parallel sequencing of methyl-binding domain enriched DNA and microarray-based RNA expression profiling of 5-aza-2'-deoxycytidine-treated ccRCC cell lines to comprehensively characterize the ccRCC methylome. A selection of the identified methylation markers was evaluated in two independent series of primary ccRCC (n= 150 andn= 185) by methylation-specific PCR. Kaplan-Meier curves and log-rank tests were used to estimate cause-specific survival. HRs and corresponding 95% confidence intervals (CI) were assessed using Cox proportional hazard models. To assess the predictive capacity and fit of models combining several methylation markers, HarrellCstatistic and the Akaike Information Criterion were used.Results:We identified four methylation markers, that is,GREM1, NEURL, LAD1,andNEFH, that individually predicted prognosis of patients with ccRCC. The four markers combined were associated with poorer survival in two independent patient series (HR, 3.64; 95% CI, 1.02-13.00 and HR, 7.54; 95% CI, 2.68-21.19). These findings were confirmed in a third series of ccRCC cases from The Cancer Genome Atlas (HR, 3.60; 95% CI, 2.02-6.40).Conclusions:A four-gene promoter methylation marker panel consisting ofGREM1, NEURL, LAD1,andNEFHpredicts outcome of patients with ccRCC and might be used to improve current prognostic models.Clin Cancer Res; 23(8); 2006-18. ©2016 AACR.
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Iris J H
authors.initials: IJH
authors.lastname: van Vlodrop
authors.affiliation: Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Sophie C
authors.initials: SC
authors.lastname: Joosten
authors.affiliation: BioBix: Laboratory of Bioinformatics and Computational Genomics, Department of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: De Meyer
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.|Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Smits
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Veerle
authors.initials: V
authors.lastname: Melotte
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Marcella M L L
authors.initials: MMLL
authors.lastname: Baldewijns
authors.affiliation: Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Schouten
authors.affiliation: Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.|Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jana
authors.initials: J
authors.lastname: Jeschke
authors.affiliation: Research Institute, Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Jangan-eup, Gijang-gun, Busan, Korea.
authors.forename: Joo Mi
authors.initials: JM
authors.lastname: Yi
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Kornel E
authors.initials: KE
authors.lastname: Schuebel
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.affiliation: Hillman Cancer Center, Pittsburgh, Pennsylvania.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Division of Medical Oncology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Aarts
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Fred T
authors.initials: FT
authors.lastname: Bosman
authors.affiliation: BioBix: Laboratory of Bioinformatics and Computational Genomics, Department of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Criekinge
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands. manon.van.engeland@mumc.nl.
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
mesh_terms: D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality; D019175:DNA Methylation / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016900:Neurofilament Proteins / Q000235:genetics; D024041:Non-Fibrillar Collagens / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D014408:Biomarkers, Tumor; D036341:Intercellular Signaling Peptides and Proteins; D016900:Neurofilament Proteins; D024041:Non-Fibrillar Collagens; D044767:Ubiquitin-Protein Ligases; D000097805:Collagen Type XVII; C486399:GREM1 protein, human; C051774:neurofilament protein H; C556508:NEURL1 protein, human