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dc.contributor.authorWeigelt, B
dc.contributor.authorComino-Méndez, I
dc.contributor.authorde Bruijn, I
dc.contributor.authorTian, L
dc.contributor.authorMeisel, JL
dc.contributor.authorGarcía-Murillas, I
dc.contributor.authorFribbens, C
dc.contributor.authorCutts, R
dc.contributor.authorMartelotto, LG
dc.contributor.authorNg, CKY
dc.contributor.authorLim, RS
dc.contributor.authorSelenica, P
dc.contributor.authorPiscuoglio, S
dc.contributor.authorAghajanian, C
dc.contributor.authorNorton, L
dc.contributor.authorMurali, R
dc.contributor.authorHyman, DM
dc.contributor.authorBorsu, L
dc.contributor.authorArcila, ME
dc.contributor.authorKonner, J
dc.contributor.authorReis-Filho, JS
dc.contributor.authorGreenberg, RA
dc.contributor.authorRobson, ME
dc.contributor.authorTurner, NC
dc.date.accessioned2017-11-22T11:40:28Z
dc.date.issued2017-11
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (21), pp. 6708 - 6720
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/924
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-17-0544
dc.description.abstractPurpose: Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or PARP inhibitors. Experimental Design: cfDNA from 24 prospectively accrued patients with germline BRCA1 or BRCA2 mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2 Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function. Results: Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function. Conclusions: Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in patients with ovarian and breast cancer. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy. Clin Cancer Res; 23(21); 6708-20. ©2017 AACR .
dc.formatPrint-Electronic
dc.format.extent6708 - 6720
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectOvarian Neoplasms
dc.subjectPlatinum
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectGerm-Line Mutation
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectPoly(ADP-ribose) Polymerase Inhibitors
dc.subjectCell-Free Nucleic Acids
dc.titleDiverse <i>BRCA1</i> and <i>BRCA2</i> Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer.
dc.typeJournal Article
dcterms.dateAccepted2017-07-28
rioxxterms.funderThe Institute of Cancer Research
rioxxterms.identifier.projectUnspecified
rioxxterms.versionofrecord10.1158/1078-0432.ccr-17-0544
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2017-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue21
pubs.notesNot known
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/Molecular Oncology
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/Molecular Oncology
pubs.publication-statusPublished
pubs.volume23
pubs.embargo.termsNot known
icr.researchteamMolecular Oncologyen_US
dc.contributor.icrauthorTurner, Nicholasen
dc.contributor.icrauthorGarcia-Murillas, Isaacen


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