title: Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors.affiliation: 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).
authors.forename: Grant D
authors.initials: GD
authors.lastname: Stewart
authors.affiliation: 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).
authors.forename: Fiach C
authors.initials: FC
authors.lastname: O'Mahony
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Laird
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Lel
authors.initials: L
authors.lastname: Eory
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Alexander L R
authors.initials: AL
authors.lastname: Lubbock
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.affiliation: 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).
authors.forename: Jyoti
authors.initials: J
authors.lastname: Nanda
authors.affiliation: 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).
authors.forename: Marie
authors.initials: M
authors.lastname: O'Donnell
authors.affiliation: School of Medicine, University of St. Andrews, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Mullen
authors.affiliation: 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).
authors.forename: S Alan
authors.initials: SA
authors.lastname: McNeill
authors.affiliation: 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).
authors.forename: Antony C P
authors.initials: AC
authors.lastname: Riddick
authors.affiliation: Department of Molecular Oncology, Bart's Cancer Institute, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Berney
authors.affiliation: Department of Urology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: Bex
authors.affiliation: Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC). Renal Cancer Unit, The Royal Free Hospital, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Aitchison
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Overton
authors.affiliation: Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC). School of Medicine, University of St. Andrews, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000473:pathology*; D017322:Clinical Trials, Phase II as Topic; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins; D015195:Drug Design; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D000860:Hypoxia; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009392:Nephrectomy; D009687:Nuclear Proteins / Q000378:metabolism; D010865:Pilot Projects; D040081:Protein Array Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D000077210:Sunitinib; D014157:Transcription Factors / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D004268:DNA-Binding Proteins; D007211:Indoles; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D000077210:Sunitinib