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.
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.
Our data provide the first mapping of methylome epi-signature and indicates 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 three fold more hypermethylation as compared to 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.
Our data defines 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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Jun 02 [Epub ahead of print]
Gabriel G Malouf, Xiaoping Su, Jianping Zhang, Chad J Creighton, Thai H Ho, Yue Lu, Noël J-M Raynal, Jose A Karam, Pheroze Tamboli, Frederick Allanick, Roger Mouawad, Jean-Philippe Spano, David Khayat, Christopher G Wood, Jaroslav Jelinek, Nizar M Tannir
Medical Oncology, Hôpital de la Pitié-Salpétriêre., Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center., Bioinformatics & Comp Biology, The University of Texas MD Anderson Cancer Center., Department of Medicine, Baylor College of Medicine., Division of Hematology and Medical Oncology, Mayo Clinic., Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center., Molecular Biology, Fels Institute., Genitourinary Medical Oncology, UT M. D. Anderson Cancer Center., Genitourinary Medical Oncology, UT M. D. Anderson Cancer Center., N/A, AVEC Foundation Laboratory., Medical Oncology Department, AP-HP, Salpêtrière Hospital, University of Pierre & Marie Curie Paris 6., Oncology, Pitie-Salpetriere Hospital., Genitourinary Medical Oncology, UT M. D. Anderson Cancer Center., Fels Institute for Cancer and Molecular Biology, Temple University School of Medicine., Genitourinary Medical Oncology, UT M. D. Anderson Cancer Center .