title: Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes.
abstract: Current 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.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.
authors.forename: Pascale
authors.initials: P
authors.lastname: Fisel
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Büttner
authors.affiliation: Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Rausch
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.
authors.forename: Debora
authors.initials: D
authors.lastname: D'Amico
authors.affiliation: Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hennenlotter
authors.affiliation: Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kruck
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nies
authors.affiliation: Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.affiliation: Department of Urology and Pediatric Urology, Saarland University Medical Center and Saarland University Faculty of Medicine, Kirrberger Straße, 66421 Homburg/Saar, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Junker
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Tuebingen, Liebermeisterstr. 8, 72076 Tuebingen, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Scharpf
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: van der Kuip
authors.affiliation: Institute of Pathology and Neuropathology, University Hospital Tuebingen, Liebermeisterstr. 8, 72076 Tuebingen, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.affiliation: Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Auerbachstr. 110, 70376 Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Institute of Pathology, University Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Institute of Pathology, University Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Bedke
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Clinical Pharmacology, University Hospital Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010597:Pharmacogenetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger