EGAGenomicsMatthias Schwabhttps://ega-archive.org/dacs/EGAC00001000317EGAEGA DAC EGAC00001000317EGAMatthias.Schwab@ikp-stuttgart.deCurrent therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs ≥ 0.92). However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0.05) in five established RCC cell lines compared to primary tumors, resulting in altered transcriptional expression. Exemplarily, gene-specific analyses of DNA methylation, mRNA and protein expression demonstrate lack of expression of the clinically important drug transporter OCT2 (encoded by SLC22A2) in cell lines due to hypermethylation compared to tumors or metastases. Our findings provide evidence that RCC cell lines are of limited benefit for prediction of drug effects due to epigenetic alterations. Similar epigenetic landscape of ccRCC-metastases and tumors opens new avenue for future therapeutic strategies.Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes.Winter Stefan S, Fisel Pascale P, Büttner Florian F, Rausch Steffen S, D'Amico Debora D, Hennenlotter Jörg J, Kruck Stephan S, Nies Anne T AT, Stenzl Arnulf A, Junker Kerstin K, Scharpf Marcus M, Hofmann Ute U, van der Kuip Heiko H, Fend Falko F, Ott German G, Agaimy Abbas A, Hartmann Arndt A, Bedke Jens J, Schwab Matthias M, Schaeffeler Elke Eimprinted and ancient gene protein, Malignant Neoplasm, Malignancy, Neoplasms, impact-a., Benign Neoplasm, Cell Lines, Benign Neoplasms, Cancers, Tumor, Malignant, Ximpact, Cell, Malignant Neoplasms, Neoplasias, Benign, Line, Neoplasm, imprinted and ancient gene protein homolog, IMPACT, Malignancies, E430016J11Rik, Neoplasia, RWDD5, Lines, Cancer, Tumorsfbwd4, l(2)04454, DmelCG1772, dac, CIB1, shsf3, shfm3, Decapo., E(Sev-CycE)2B, p21[dacapo], Fbw4, FBW4, dactylin, E130112M23Rik, Dach, CDKN2B, cdi4, SHFM3, Dac, DAC, p27[Dap], dactylyn, dacapo/cyclin-dependent kinase interactor 4, AI182278, p21, CG1772, FBWD4, Dap, Cdi4, CDI4, CES5A1, p27, P15, fbw4, SHSF3Adenocarcinoma, Materials, pdm-2, Collecting Duct, clear cell renal cell adenocarcinoma, Product, Neoplasms, Renal Cell Cancers, Benign Neoplasm, Gene, adenocarcinoma of kidney, OCT2, DNA Methylations, protein, Oct2, Renal Adenocarcinomas, Development, Medication, broad, Tumor, protein-containing complex, Papillary Renal Cell Carcinoma, Pharmaceutical Development, Malignant, CCRCC, Oct-2, miti, Hypernephroid, Adenocarcinoma Of Kidneys, Renal Cell Adenocarcinomas, dPOU28, Messenger, Sarcomatoid Renal Cell Carcinoma, Pharmaceutical Product, Line, Gene Products, dOct2, symptoms, Hypernephroid Carcinomas, RCC, Renal Carcinomas, Hypernephroid Carcinoma, Drug Target Prediction, protein aggregate, hypernephroma, Non Polyadenylated, dpou28, Grawitz Tumor, CG12287, Drugs, Hypernephromas, DNA methylation maintenance, Genetic, Genomes, Malignancy, Polyadenylated Messenger, Collecting Duct Carcinoma, dPOU-28, Medication Development, messenger RNA, Renal, DNA methylation, Pdm2, Epigenomic, Neoplasias, clear cell renal cell carcinoma, template RNA, drugs, medicine, Pharmaceutical, Renal Collecting Duct Carcinoma, Malignancies, OTF2, Preparation, Collecting Duct Carcinomas (Kidney), Methylations, Grawitz, Cancer, Pharmaceuticals, Tumors, Products, screening, Carcinoma, dPOU28/pdm-2, RNA, Adenocarcinoma Of, findings, wide/broad, Malignant Neoplasm, dim, Polyadenylated, protein complex, Chromophil Renal Cell Carcinoma, Collecting Duct Carcinomas, drug, Proteins, Cell Lines, Renal Cell Carcinomas, Messenger RNA, Renal Cell Adenocarcinoma, Renal Adenocarcinoma, Adenocarcinoma Of Kidney, Medications, Cistrons, Renal Cell Carcinoma, Adenocarcinomas, DNA methylation profiling, Cell, CG15486, CG15487, Chromophobe Renal Cell Carcinoma, Collecting Duct Carcinoma of the Kidney, renal cell adenocarcinoma, Clear Cell Renal Cell Carcinoma, Prediction, Benign, native protein, Pdm-2, Poly(A)+ mRNA, Protein, Neoplasm, INSDC_feature:mRNA, Genetic Materials, Pharmaceutic, Nephroid Carcinomas, methylation, Polyadenylated RNA, Hypernephroma, Genetic Material, pharmacologic effects, Target Prediction, Drug Target Predictions, Lines, Carcinomas, Polyadenylated Messenger RNA, Poly(A)+ RNA, kidney adenocarcinoma, Non Polyadenylated mRNA, protein_coding_transcript, effect of drugs, Pharmaceutic Preparations, mRNA, Poly(A) Tail, DmelCG12287, Epigenetic, Renal Cell, Renal Carcinoma, Kidney, Non-Polyadenylated, signs, Benign Neoplasms, INSDC_feature:gene, whole genome, Cancers, Pdm, Nephroid, Clear-cell metastatic renal cell carcinoma, Non-Polyadenylated mRNA, Renal Cell Cancer, Malignant Neoplasms, Drug, Protein Gene Products, Papillary, Gene Proteins, Computational Prediction of Drug-Target Interactions, metastatic, Preparations, wide, Material, Collecting Duct Carcinoma (Kidney), Collecting Duct (Kidney), Drug Target, renal cell carcinoma, Cistron, DNA, pdm, Epigenetics, Pharmaceutical Products, Polyadenylated mRNA, Nephroid Carcinoma, Poly(A) RNA, Neoplasia, Methylation, Pharmaceutical Preparation, Clear Cell Renal Carcinoma, Malignant Neoplasms.falseDAC for Tuebingen-Stuttgart cohortData Access Committee EGAC00001000317EGAC00001000317960627435027EGAS00001001176EGAD00010002323EGAD00010002392EGAD00010002352EGAD00010001589EGAD00010001564EGAD00010001001EGAD00010002353