Research Papers:
Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer
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Abstract
Grant D. Stewart1,2,9,*, Thomas Powles3,4,*, Christophe Van Neste5,*, Alison Meynert6, Fiach O’Mahony1,2, Alexander Laird1,2,6, Dieter Deforce5, Filip Van Nieuwerburgh5, Geert Trooskens7, Wim Van Criekinge7, Tim De Meyer7 and David J. Harrison2,8
1 Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
2 Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC), Scotland, UK
3 Renal Cancer Unit, The Royal Free Hospital, London, UK
4 Centre for Experimental Cancer Medicine, Bart’s Cancer Institute, Queen Mary University of London, London, UK
5 Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
6 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
7 Biobix: Laboratory of Bioinformatics and Computational Genomics, Department of Mathematical Modeling, Statistics and Bioinformatics, Ghent University, Ghent, Belgium
8 School of Medicine, University of St Andrews, Fife, UK
9 Academic Urology Group, University of Cambridge, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Cambridge, UK
* joint 1st authors
Correspondence to:
Thomas Powles, email:
Keywords: heterogeneity, methylation, mutations, renal cancer, VHL
Received: December 30, 2015 Accepted: March 10, 2016 Published: March 23, 2016
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 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; 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 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.
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