Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/117606
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Type: Journal article
Title: Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease
Author: Branford, S.
Wang, P.
Yeung, D.
Thomson, D.
Purins, A.
Wadham, C.
Shahrin, N.
Marum, J.
Nataren, N.
Parker, W.
Geoghegan, J.
Feng, J.
Shanmuganathan, N.
Mueller, M.
Dietz, C.
Stangl, D.
Donaldson, Z.
Altamura, H.
Georgievski, J.
Braley, J.
et al.
Citation: Blood, 2018; 132(9):948-961
Publisher: American Society of Hematology
Issue Date: 2018
ISSN: 0006-4971
1528-0020
Statement of
Responsibility: 
Susan 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. Hughes
Abstract: Genomic 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.
Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Disease-Free Survival; Female; Follow-Up Studies; Genomics; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Neoplasm Proteins; Philadelphia Chromosome; Risk Factors; Survival Rate; Translocation, Genetic
Rights: © 2018 by The American Society of Hematology
RMID: 0030096917
DOI: 10.1182/blood-2018-02-832253
Grant ID: http://purl.org/au-research/grants/nhmrc/1027531
http://purl.org/au-research/grants/nhmrc/1104425
http://purl.org/au-research/grants/nhmrc/1135949
http://purl.org/au-research/grants/nhmrc/1023059
http://purl.org/au-research/grants/nhmrc/1146253
Appears in Collections:Medicine publications

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