title: Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy.
abstract: Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution.
authors.affiliation: Department of Computer Science.|The Donnelly Centre for Cellular and Biomolecular Research, and.
authors.forename: TaeHyung
authors.initials: T
authors.lastname: Kim
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, and.|The Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Tyndel
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.|Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea; and.
authors.forename: Hyeoung Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.|Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea; and.
authors.forename: Jae-Sook
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.
authors.forename: Yeo-Kyeoung
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Faculty of Medicine and.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.affiliation: Department of Computer Science.|The Donnelly Centre for Cellular and Biomolecular Research, and.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhaolei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Faculty of Medicine and.
authors.forename: Dennis Dong Hwan
authors.initials: DD
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors