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Clin Cancer Res. 2016 Dec 15;22(24):6236-6246. Epub 2016 Jun 2.

DNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas.

Author information

1
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.
2
AVEC Foundation Laboratory, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
3
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Medicine, Baylor College of Medicine, Houston, Texas.
5
Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona.
6
Center for Individualized Medicine, Epigenomics Group, Mayo Clinic, Rochester, Minnesota.
7
Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.
8
Fels Institute, Temple University School of Medicine, Philadelphia, Pennsylvania.
9
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, University Pierre and Marie Curie (Paris VI), Institut Universitaire de cancérologie, AP-HP, Paris, France.
12
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. ntannir@mdanderson.org gabriel.malouf@psl.aphp.fr.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGNS:

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.

PMID:
27256309
PMCID:
PMC5135666
DOI:
10.1158/1078-0432.CCR-15-1217
[Indexed for MEDLINE]
Free PMC Article

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