title: The clonal origins of leukemic progression of myelodysplasia.
abstract: The genetics behind the progression of myelodysplasia to secondary acute myeloid leukemia (sAML) is poorly understood. In this study, we profiled somatic mutations and their dynamics using next generation sequencing on serial samples from a total of 124 patients, consisting of a 31 patient discovery cohort and 93 patients from two validation cohorts. Whole-exome analysis on the discovery cohort revealed that 29 of 31 patients carry mutations related to at least one of eight commonly mutated pathways in AML. Mutations in genes related to DNA methylation and splicing machinery were found in T-cell samples, which expand at the initial diagnosis of the myelodysplasia, suggesting their importance as early disease events. On the other hand, somatic variants associated with signaling pathways arise or their allelic burdens expand significantly during progression. Our results indicate a strong association between mutations in activated signaling pathways and sAML progression. Overall, we demonstrate that distinct categories of genetic lesions play roles at different stages of sAML in a generally fixed order.
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, ON, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Kim
authors.affiliation: The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.|The Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, ON, Canada.
authors.forename: M 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.
authors.forename: H J
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.
authors.forename: J-S
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.|Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
authors.forename: Y-K
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
authors.forename: D-H
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Genome Research Center for Hematopoietic Disease, Chonnam National University, Hwasun, Korea.|Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University, Seoul, Korea.
authors.forename: Y H
authors.initials: YH
authors.lastname: Min
authors.affiliation: Department of Internal Medicine, Yonsei University, Seoul, Korea.
authors.forename: J-W
authors.initials: JW
authors.lastname: Cheong
authors.affiliation: Department of Hematology-Oncology, Kyungpook National University, Daegu, Korea.
authors.forename: S K
authors.initials: SK
authors.lastname: Sohn
authors.affiliation: Department of Hematology-Oncology, Kyungpook National University, Daegu, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: M
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: M
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, ON, Canada.|The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: D D H
authors.initials: DDH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002999:Clone Cells / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics; D017381:Spliceosomes / Q000235:genetics