biostudies-literatureMalouf GGNCI NIH HHS6236-6246https://www.ebi.ac.uk/biostudies/studies/S-EPMC5135666biostudies-literatureUnknown22(24)<h4>Purpose</h4>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.<h4>Experimental designs</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Clinical cancer research : an official journal of the American Association for Cancer ResearchDNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas.PMC5135666P30 CA016672P30 CA015083P30 CA006927K12 CA090628P30 CA125123Raynal NJAllanick FSpano JPHo THZhang JWood CGLu YMalouf GGKaram JACreighton CJJelinek JTamboli PTannir NMMouawad RKhayat DSu XfalseDNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas.<h4>Purpose</h4>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.<h4>Experimental designs</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.2016-01-01T00:00:00Z2016 Dec2024-11-06T01:18:54.447Z2019-03-27T02:30:43ZS-EPMC51356662725630910.1158/1078-0432.CCR-15-121710.1158/1078-0432.ccr-15-1217