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dc.contributor.authorCroft, J
dc.date.accessioned2022-05-17T13:26:34Z
dc.date.available2023-05-31T00:00:00Z
dc.date.issued2022-05-31
dc.identifier.citation2022en
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5133
dc.description.abstractBetter understanding of the mechanisms of relapse and treatment resistance in myeloma could improve clinical outcomes. Copy number aberrations (CNA) are a major feature of multiple myeloma, however their evolution over time in the context of modern biological therapy is not well characterised. To investigate acquisition of CNA and their prognostic relevance in the context of first-line therapy, I have profiled paired tumour samples at diagnosis-relapse from NCRI Myeloma XI (ISCRTN4907852) trial patients using digital multiplex ligation-dependent probe amplification. To facilitate identification of driver genes and molecular pathways associated with CNA evolution at relapse, sequential gene expression profiles were also analysed using the affymetrix HGU133 plus 2.0 array. CNA profiles acquired at relapse differed substantially between myeloma subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs linear pattern in t(4;14) vs stable pattern in t(11;14). CNA acquisition also differed between subtypes based on cyclin D expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNA were not influenced by high-dose melphalan or lenalidomide maintenance randomisation. A branching evolution pattern was associated with a significantly inferior overall survival. Acquisition of gain(1q) at relapse was the most common new CNA to evolve at relapse and associated with significantly shorter OS, independent of other risk factors or time of relapse. High risk signatures increased at relapse in the majority of tumours. Gene set enrichment analysis highlighted mechanisms of tumour proliferation and leading edge analysis highlighted the role of XPO1 inhibition in treating relapsed myeloma. No significant gene set enrichment at relapse in relation to high-dose melphalan or lenalidomide maintenance randomization was identified. There is an increasing need for rational therapy sequencing in myeloma. This data supports the value of repeat molecular profiling to characterise disease evolution and inform management of relapsing myeloma.en_US
dc.languageeng
dc.language.isoeng
dc.publisherInstitute of Cancer Research (University Of London)
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectTheses, Doctoralen_US
dc.subjectMultiple Myeloma - Geneticsen_US
dc.subjectMultiple Myeloma - Therapyen_US
dc.titleGenetics of relapse and treatment resistance in multiple myelomaen
dc.typeThesis or Dissertation
dcterms.accessRightsPublic
dcterms.licensehttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.versionAO
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2022-05-31
rioxxterms.typeThesis
pubs.notes12 monthsen_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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Myeloma Group
pubs.embargo.terms12 monthsen_US
pubs.embargo.date2023-05-31T00:00:00Z
icr.researchteamMyeloma Group
dc.contributor.icrauthorCroft, Jamesen_US
uketdterms.institutionInstitute of Cancer Research
uketdterms.qualificationlevelMasters
uketdterms.qualificationnameM.D.Res
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameM.D.Res


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