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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer
Grant D Stewart1,2,3, Thomas Powles4,5, Christophe Van Neste6
1Edinburgh Urological Cancer Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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.
Insights
Epigenetic profiling in metastatic clear cell renal cancer (mccRCC) reveals consistent VHL hypermethylation after sunitinib treatment, suggesting a potential biomarker despite genetic heterogeneity.
Area of Science:
- Oncology
- Genomics
- Epigenetics
Background:
- Genetic intratumoral heterogeneity (ITH) complicates biomarker development for metastatic clear cell renal cancer (mccRCC).
- Epigenetic ITH and treatment-induced epigenetic changes in mccRCC remain largely unevaluated.
- This study aimed to assess methylome/genetic ITH and identify epigenetic/genetic alterations linked to sunitinib therapy.
Purpose of the Study:
- To determine the extent of methylome and genetic intratumoral heterogeneity in mccRCC.
- To evaluate specific epigenetic and genetic changes occurring after sunitinib treatment in mccRCC patients.
- To explore the potential of epigenetic markers as reliable biomarkers in the context of ITH.
Main Methods:
- Multi-region DNA sampling from 14 mccRCC patients before and after sunitinib therapy.
- Analysis of 48 key ccRCC genes using Ion Proton sequencing.
- DNA methylation analysis using MethylCap-seq, with data analyzed in R.
Main Results:
- Methylome analysis showed complete sample clustering by patient, indicating relative methylome homogeneity.
- VHL promoter region 7896829 was consistently hypermethylated following sunitinib treatment (P<0.001).
- No significant changes in driver or private mutation counts were observed with sunitinib treatment.
Conclusions:
- Relative methylome homogeneity was demonstrated in mccRCC.
- Consistent VHL hypermethylation after sunitinib treatment offers a potential biomarker strategy.
- This epigenetic consistency may help overcome challenges posed by genetic ITH in biomarker research.
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