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Clin Cancer Res. 2015 Sep 15;21(18):4212-23. doi: 10.1158/1078-0432.CCR-15-0207. Epub 2015 May 26.

Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer.

Author information

1
Edinburgh Urological Cancer Group, Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC).
2
Edinburgh Urological Cancer Group, Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom. Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC). MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
3
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
4
Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom.
5
School of Medicine, University of St. Andrews, United Kingdom.
6
Department of Molecular Oncology, Bart's Cancer Institute, London, United Kingdom.
7
Department of Urology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
8
Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC). Renal Cancer Unit, The Royal Free Hospital, London, United Kingdom.
9
Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC). School of Medicine, University of St. Andrews, United Kingdom.
10
Renal Cancer Unit, The Royal Free Hospital, London, United Kingdom. Centre for Experimental Cancer Medicine, Bart's Cancer Institute, Queen Mary University of London, United Kingdom. thomas.powles@bartshealth.nhs.uk.

Abstract

PURPOSE:

The aim of this study was to investigate the effect of VEGF-targeted therapy (sunitinib) on molecular intratumoral heterogeneity (ITH) in metastatic clear cell renal cancer (mccRCC).

EXPERIMENTAL DESIGN:

Multiple tumor samples (n = 187 samples) were taken from the primary renal tumors of patients with mccRCC who were sunitinib treated (n = 23, SuMR clinical trial) or untreated (n = 23, SCOTRRCC study). ITH of pathologic grade, DNA (aCGH), mRNA (Illumina Beadarray) and candidate proteins (reverse phase protein array) were evaluated using unsupervised and supervised analyses (driver mutations, hypoxia, and stromal-related genes). ITH was analyzed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene-expression clustering.

RESULTS:

Tumor grade heterogeneity was greater in treated compared with untreated tumors (P = 0.002). In unsupervised analysis, sunitinib therapy was not associated with increased ITH in DNA or mRNA. However, there was an increase in ITH for the driver mutation gene signature (DNA and mRNA) as well as increasing variability of protein expression with treatment (P < 0.05). Despite this variability, significant chromosomal and transcript changes to key targets of sunitinib, such as VHL, PBRM1, and CAIX, occurred in the treated samples.

CONCLUSIONS:

These findings suggest that sunitinib treatment has significant effects on the expression and ITH of key tumor and treatment specific genes/proteins in mccRCC. The results, based on primary tumor analysis, do not support the hypothesis that resistant clones are selected and predominate following targeted therapy.

PMID:
26015515
DOI:
10.1158/1078-0432.CCR-15-0207
[Indexed for MEDLINE]
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