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Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer

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Date
23/03/2016
Author
Stewart, Grant D.
Powles, Thomas
Van Neste, Christophe
Meynert, Alison
O'Mahony, Fiach
Laird, Alexander
Deforce, Dieter
Van Nieuwerburgh, Filip
Trooskens, Geert
Van Criekinge, Wim
De Meyer, Tim
Harrison, David James
Keywords
Heterogeneity
Methylation
Mutations
Renal cancer
VHL
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
NDAS
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Abstract
Background: 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 ITH of the methylome relative to genetic ITH and to evaluate specific epigenetic and genetic changes associated with sunitinib. 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; ClinicalTrials.gov 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 R. Results: Unsupervised hierarchical clustering revealed complete methylomeclustering 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. 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 found with sunitinib treatment. Conclusions: Demonstration of methylome homogeneity and consistent VHL hypermethylation, after sunitinib, overcome the hurdle of ITH present at other molecular levels.
Citation
Stewart , G D , Powles , T , Van Neste , C , Meynert , A , O'Mahony , F , Laird , A , Deforce , D , Van Nieuwerburgh , F , Trooskens , G , Van Criekinge , W , De Meyer , T & Harrison , D J 2016 , ' Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer ' , Oncotarget , vol. 7 , no. 18 . https://doi.org/10.18632/oncotarget.8308
Publication
Oncotarget
Status
Peer reviewed
DOI
https://doi.org/10.18632/oncotarget.8308
ISSN
1949-2553
Type
Journal article
Rights
Licensed under a Creative Commons Attribution 3.0 License
Description
This 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) and an educational grant from Pfizer (to TP).
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/8558

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