Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/117606
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dc.contributor.authorBranford, S.en
dc.contributor.authorWang, P.en
dc.contributor.authorYeung, D.en
dc.contributor.authorThomson, D.en
dc.contributor.authorPurins, A.en
dc.contributor.authorWadham, C.en
dc.contributor.authorShahrin, N.en
dc.contributor.authorMarum, J.en
dc.contributor.authorNataren, N.en
dc.contributor.authorParker, W.en
dc.contributor.authorGeoghegan, J.en
dc.contributor.authorFeng, J.en
dc.contributor.authorShanmuganathan, N.en
dc.contributor.authorMueller, M.en
dc.contributor.authorDietz, C.en
dc.contributor.authorStangl, D.en
dc.contributor.authorDonaldson, Z.en
dc.contributor.authorAltamura, H.en
dc.contributor.authorGeorgievski, J.en
dc.contributor.authorBraley, J.en
dc.contributor.authoret al.en
dc.date.issued2018en
dc.identifier.citationBlood, 2018; 132(9):948-961en
dc.identifier.issn0006-4971en
dc.identifier.issn1528-0020en
dc.identifier.urihttp://hdl.handle.net/2440/117606-
dc.description.abstractGenomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole-exome sequencing, copy-number variation, and/or RNA sequencing for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six patients with chronic-phase disease with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15 (56%) of 27 patients with subsequent BC or poor outcome and in 3 (16%) of 19 optimal responders (P = .007). Frequently mutated genes at diagnosis were ASXL1, IKZF1, and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene. A novel class of variant associated with the Philadelphia (Ph) translocation was detected at diagnosis in 11 (24%) of 46 patients comprising fusions and/or rearrangement of genes on the translocated chromosomes, with evidence of fragmentation, inversion, and imperfect sequence reassembly. These were more frequent at diagnosis in patients with poor outcome: 9 (33%) of 27 vs 2 (11%) of 19 optimal responders (P = .07). Thirty-nine patients were tested at BC, and all had cancer gene variants, including ABL1 kinase domain mutations in 58%. However, ABL1 mutations cooccurred with other mutated cancer genes in 89% of cases, and these predated ABL1 mutations in 62% of evaluable patients. Gene fusions not associated with the Ph translocation occurred in 42% of patients at BC and commonly involved fusion partners that were known cancer genes (78%). Genomic analysis revealed numerous relevant variants at diagnosis in patients with poor outcome and all patients at BC. Future refined biomarker testing of specific variants will likely provide prognostic information to facilitate a risk-adapted therapeutic approach.en
dc.description.statementofresponsibilitySusan Branford … David T. Yeung … Naranie Shanmuganathan … Christopher Hahn … Deborah L. White, Agnes S.M. Yong, David M. Ross, Hamish S. Scott, Andreas W. Schreiber, and Timothy P. Hughesen
dc.language.isoenen
dc.publisherAmerican Society of Hematologyen
dc.rights© 2018 by The American Society of Hematologyen
dc.titleIntegrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk diseaseen
dc.typeJournal articleen
dc.identifier.rmid0030096917en
dc.identifier.doi10.1182/blood-2018-02-832253en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1027531en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1104425en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1135949en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1023059en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1146253en
dc.identifier.pubid436272-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS14en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidHahn, C. [0000-0001-5105-2554]en
dc.identifier.orcidWhite, D. [0000-0003-4844-333X]en
dc.identifier.orcidYong, A. [0000-0001-9452-1533]en
dc.identifier.orcidRoss, D. [0000-0001-7171-2935]en
dc.identifier.orcidScott, H. [0000-0002-5813-631X]en
dc.identifier.orcidSchreiber, A. [0000-0002-9081-3405]en
dc.identifier.orcidHughes, T. [0000-0002-0910-3730]en
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