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dc.contributor.authorKhalique, Sen_US
dc.contributor.authorNaidoo, Ken_US
dc.contributor.authorAttygalle, ADen_US
dc.contributor.authorKriplani, Den_US
dc.contributor.authorDaley, Fen_US
dc.contributor.authorLowe, Aen_US
dc.contributor.authorCampbell, Jen_US
dc.contributor.authorJones, Ten_US
dc.contributor.authorHubank, Men_US
dc.contributor.authorFenwick, Ken_US
dc.contributor.authorMatthews, Nen_US
dc.contributor.authorRust, AGen_US
dc.contributor.authorLord, CJen_US
dc.contributor.authorBanerjee, Sen_US
dc.contributor.authorNatrajan, Ren_US
dc.date.accessioned2018-06-08T08:51:09Z
dc.date.issued2018-07-20en_US
dc.identifier.citationThe journal of pathology. Clinical research, 2018, 4 (3), pp. 154 - 166en_US
dc.identifier.issn2056-4538en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1757
dc.identifier.eissn2056-4538en_US
dc.identifier.doi10.1002/cjp2.103en_US
dc.description.abstractARID1A is a tumour suppressor gene that is frequently mutated in clear cell and endometrioid carcinomas of the ovary and endometrium and is an important clinical biomarker for novel treatment approaches for patients with ARID1A defects. However, the accuracy of ARID1A immunohistochemistry (IHC) as a surrogate for mutation status has not fully been established for patient stratification in clinical trials. Here we tested whether ARID1A IHC could reliably predict ARID1A mutations identified by next-generation sequencing. Three commercially available antibodies - EPR13501 (Abcam), D2A8U (Cell Signaling), and HPA005456 (Sigma) - were optimised for IHC using cell line models and human tissue, and screened across a cohort of 45 gynaecological tumours. IHC was scored independently by three pathologists using an immunoreactive score. ARID1A mutation status was assessed using two independent sequencing platforms and the concordance between ARID1A mutation and protein expression was evaluated using Receiver Operating Characteristic statistics. Overall, 21 ARID1A mutations were identified in 14/43 assessable tumours (33%), the majority of which were predicted to be deleterious. Mutations were identified in 6/17 (35%) ovarian clear cell carcinomas, 5/8 (63%) ovarian endometrioid carcinomas, 2/5 (40%) endometrial carcinomas, and 1/7 (14%) carcinosarcomas. ROC analysis identified greater than 95% concordance between mutation status and IHC using a modified immunoreactive score for all three antibodies allowing a definitive cut-point for ARID1A mutant status to be calculated. Comprehensive assessment of concordance of ARID1A IHC and mutation status identified EPR13501 as an optimal antibody, with 100% concordance between ARID1A mutation status and protein expression, across different gynaecological histological subtypes. It delivered the best inter-rater agreement between all pathologists, as well as a clear cost-benefit advantage. This could allow patients to be accurately stratified based on their ARID1A IHC status into early phase clinical trials.en_US
dc.formatPrint-Electronicen_US
dc.format.extent154 - 166en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectHumansen_US
dc.subjectAdenocarcinoma, Clear Cellen_US
dc.subjectCarcinoma, Endometrioiden_US
dc.subjectOvarian Neoplasmsen_US
dc.subjectGenital Neoplasms, Femaleen_US
dc.subjectNuclear Proteinsen_US
dc.subjectTranscription Factorsen_US
dc.subjectImmunohistochemistryen_US
dc.subjectMutationen_US
dc.subjectAdulten_US
dc.subjectAgeden_US
dc.subjectMiddle Ageden_US
dc.subjectFemaleen_US
dc.subjectYoung Adulten_US
dc.subjectBiomarkers, Tumoren_US
dc.titleOptimised ARID1A immunohistochemistry is an accurate predictor of ARID1A mutational status in gynaecological cancers.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-04-10en_US
rioxxterms.versionofrecord10.1002/cjp2.103en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-07-20en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfThe journal of pathology. Clinical researchen_US
pubs.issue3en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Target Validation and DNA Damage Response
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublisheden_US
pubs.volume4en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTarget Validation and DNA Damage Responseen_US
icr.researchteamFunctional Genomicsen_US
icr.researchteamGene Functionen_US
icr.researchteamTranslational Genomicsen_US
dc.contributor.icrauthorNatrajan, Rachaelen_US
dc.contributor.icrauthorCampbell, Jamesen_US
dc.contributor.icrauthorHubank, Michaelen_US
dc.contributor.icrauthorLord, Christopheren_US
dc.contributor.icrauthorBanerjee, Susanaen_US
dc.contributor.icrauthorKhalique, Sairaen_US
dc.contributor.icrauthorNaidoo, Kalnishaen_US


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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/