title: DNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas.
abstract: OBJECTIVE
  DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype-phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here, we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron.
  
  
  METHODS
  We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets.
  
  
  RESULTS
  Our data provide the first mapping of methylome epi-signature and indicate that RCC subtypes can be grouped into two major epi-clusters: C1, which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2, which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed 3-fold more hypermethylation as compared with C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC.
  
  
  CONCLUSIONS
  Our data define the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors. Clin Cancer Res; 22(24); 6236-46. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de cancérologie, AP-HP, Paris, France. ntannir@mdanderson.org gabriel.malouf@psl.aphp.fr.|AVEC Foundation Laboratory, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona.|Center for Individualized Medicine, Epigenomics Group, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Fels Institute, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Noël J-M
authors.initials: NJ
authors.lastname: Raynal
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pheroze
authors.initials: P
authors.lastname: Tamboli
authors.affiliation: AVEC Foundation Laboratory, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Frederick
authors.initials: F
authors.lastname: Allanick
authors.affiliation: AVEC Foundation Laboratory, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Mouawad
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de cancérologie, AP-HP, Paris, France.|AVEC Foundation Laboratory, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Spano
authors.affiliation: Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de cancérologie, AP-HP, Paris, France.|AVEC Foundation Laboratory, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ntannir@mdanderson.org gabriel.malouf@psl.aphp.fr.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
mesh_terms: D064229:Biological Ontologies; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D009399:Nephrons / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D059467:Transcriptome / Q000235:genetics