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dc.contributor.authorStewart, Grant Duncanen
dc.contributor.authorPowles, Thomasen
dc.contributor.authorvan, Neste Christopheen
dc.contributor.authorMeynert, Alisonen
dc.contributor.authorO’Mahony, Fiachen
dc.contributor.authorLaird, Alexanderen
dc.contributor.authorDeforce, Dieteren
dc.contributor.authorvan, Nieuwerburgh Filipen
dc.contributor.authorTrooskens, Geerten
dc.contributor.authorvan, Criekinge Wimen
dc.contributor.authorDe, Meyer Timen
dc.contributor.authorHarrison, David Jen
dc.description.abstractBackground: Genetic intratumoral heterogeneity (ITH) hinders biomarker development in metastatic clear cell renal cancer (mccRCC). Epigenetic relative to genetic ITH or the presence of consistent epigenetic changes following targeted therapy in mccRCC have not been evaluated. The aim of this study was to determine methylome/genetic ITH and to evaluate specific epigenetic and genetic changes associated with sunitinib therapy. Patients and methods: Multi-region DNA sampling performed on sequential frozen pairs of primary tumor tissue from 14 metastatic ccRCC patients, in the Upfront Sunitinib (SU011248) Therapy Followed by Surgery in Patients with Metastatic Renal Cancer: a Pilot Phase II Study (SuMR; identifier: NCT01024205), at presentation (biopsy) and after 3-cycles of 50mg sunitinib (nephrectomy). Untreated biopsy and nephrectomy samples before and after renal artery ligation were controls. Ion Proton sequencing of 48 key ccRCC genes, and MethylCap-seq DNA methylation analysis was performed, data was analysed using the statistical computing environment R. Results: Unsupervised hierarchical clustering revealed complete methylome clustering of biopsy and three nephrectomy samples for each patient (14/14 patients). For mutational status, untreated biopsy and all treated nephrectomy samples clustered together in 8/13 (61.5%) patients. The only methylation target significantly altered following sunitinib therapy was VHL promoter region 7896829 which was hypermethylated with treatment (FDR=0.077, P<0.001) and consistent for all patients (pre-treatment 50% patients had VHL mutations, 14% patients VHL hypermethylation). Renal artery ligation did not affect this result. No significant differences in driver or private mutation count was found with sunitinib treatment. Conclusions: Demonstration of relative methylome homogeneity and consistent VHL hypermethylation, after sunitinib, may overcome the hurdle of ITH present at other molecular levels for biomarker research.
dc.description.sponsorshipThis work was supported by: Chief Scientist Office, Scotland (grant number ETM37 to GDS and DJH); Cancer Research UK (Experimental Cancer Medicine Centre) (to TP, London and DJH, Edinburgh), Medical Research Council (to AL, DJH), Royal College of Surgeons of Edinburgh (to AL), Melville Trust (to AL), Renal Cancer Research Fund (to GDS), Kidney Cancer Scotland (to GDS), the Special Research Fund of Ghent University (grant number 01MR0410 to TDM, GT, WVC, CVN, FVN and DD) and an educational grant from Pfizer (to TP).
dc.publisherImpact Journals
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.subjectrenal canceren
dc.titleDynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal canceren
dc.description.versionThis is the final version of the article. It first appeared from Impact Journals via
dc.contributor.orcidStewart, Grant Duncan [0000-0003-3188-9140]
rioxxterms.typeJournal Article/Reviewen

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Attribution 4.0 International
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