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dc.contributor.authorPawlyn, Cen_US
dc.contributor.authorLoehr, Aen_US
dc.contributor.authorAshby, Cen_US
dc.contributor.authorTytarenko, Ren_US
dc.contributor.authorDeshpande, Sen_US
dc.contributor.authorSun, Jen_US
dc.contributor.authorFedorchak, Ken_US
dc.contributor.authorMughal, Ten_US
dc.contributor.authorDavies, FEen_US
dc.contributor.authorWalker, BAen_US
dc.contributor.authorMorgan, GJen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2018-12-04T12:46:37Z
dc.date.issued2018-07en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/29467487en_US
dc.identifier10.1038/s41375-018-0017-0en_US
dc.identifier.citationLeukemia, 2018, 32 (7), pp. 1561 - 1566en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2965
dc.identifier.eissn1476-5551en_US
dc.identifier.doi10.1038/s41375-018-0017-0en_US
dc.description.abstractPARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments.en_US
dc.format.extent1561 - 1566en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleLoss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?en_US
dc.typeJournal Article
dcterms.dateAccepted2017-12-15en_US
rioxxterms.versionofrecord10.1038/s41375-018-0017-0en_US
rioxxterms.licenseref.startdate2018-07en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfLeukemiaen_US
pubs.issue7en_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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Translational Cancer Discovery
pubs.publication-statusPublisheden_US
pubs.volume32en_US
pubs.embargo.termsNot knownen_US
icr.researchteamTranslational Cancer Discoveryen_US
dc.contributor.icrauthorPawlyn, Charlotteen_US


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