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dc.contributor.authorStewart, Grant D
dc.contributor.authorO'Mahony, Fiach
dc.contributor.authorLaird, Alexander
dc.contributor.authorEory, Lel
dc.contributor.authorLubbock, Alexander
dc.contributor.authorMackay, Alan
dc.contributor.authorNanda, Jyoti
dc.contributor.authorO'Donnell, Marie
dc.contributor.authorMullen, Peter
dc.contributor.authorMcNeill, Alan
dc.contributor.authorRiddick, Antony
dc.contributor.authorBerney, Daniel
dc.contributor.authorBex, Axel
dc.contributor.authorAitchison, Michael
dc.contributor.authorOverton, Ian M
dc.contributor.authorHarrison, David James
dc.contributor.authorPowles, Thomas
dc.date.accessioned2015-11-26T00:12:31Z
dc.date.available2015-11-26T00:12:31Z
dc.date.issued2015
dc.identifier.citationStewart , G D , O'Mahony , F , Laird , A , Eory , L , Lubbock , A , Mackay , A , Nanda , J , O'Donnell , M , Mullen , P , McNeill , A , Riddick , A , Berney , D , Bex , A , Aitchison , M , Overton , I M , Harrison , D J & Powles , T 2015 , ' Sunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal cancer ' Clinical Cancer Research , vol. In press . DOI: 10.1158/1078-0432.CCR-15-0207en
dc.identifier.issn1078-0432
dc.identifier.otherPURE: 193148604
dc.identifier.otherPURE UUID: f452f2df-8be5-4c3a-a85b-187e7763547f
dc.identifier.otherScopus: 84942880543
dc.identifier.urihttp://hdl.handle.net/10023/7852
dc.identifier.urihttp://clincancerres.aacrjournals.org/content/early/2015/05/23/1078-0432.CCR-15-0207/suppl/DC1en
dc.descriptionChief Scientist Office, Scotland (ETM37; GDS, ACPR, MA, DJH), Cancer Research UK (Experimental Cancer Medicine Centre) (TP, London and DJH, Edinburgh), Medical Research Council (AL, DJH), Royal College of Surgeons of Edinburgh (AL), Melville Trust (AL), Medical Research Council (MC_UU_12018/25; IMO), Royal Society of Edinburgh Scottish Government Fellowship cofunded by Marie Curie Actions (IMO), Renal Cancer Research Fund (GDS), Kidney Cancer Scotland (GDS) and an educational grant from Pfizer (TP).en
dc.description.abstractPurpose: 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 mccRCC patients who were sunitinib treated (n=23, SuMR clinical trial) or untreated (n=23, SCOTRRCC study). ITH of pathological 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 analysed using intratumoral protein variance distributions and distribution of individual patient aCGH and gene expression clustering. Results: Tumor grade heterogeneity was greater in treated compared to 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.en
dc.language.isoeng
dc.relation.ispartofClinical Cancer Researchen
dc.rightsCopyright © 2015, American Association for Cancer Research. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://dx.doi.org/10.1158/1078-0432.CCR-15-0207en
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectNDASen
dc.subject.lccRC0254en
dc.titleSunitinib treatment exacerbates intratumoral heterogeneity in metastatic renal canceren
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.identifier.doihttps://doi.org/10.1158/1078-0432.CCR-15-0207
dc.description.statusPeer revieweden
dc.date.embargoedUntil26-11-20


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