title: Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome.
abstract: Clinical outcome and mutations of 96 core-binding factor acute myeloid leukemia (AML) patients 18-60 years old were examined. Complete remission (CR) after induction was 94.6%. There was no significant difference in CR, leukemia-free-survival (LFS) and overall survival (OS) between t(8;21) (N=67) and inv(16) patients (N=29). Univariate analysis showed hematopoietic stem cell transplantation at CR1 as the only clinical parameter associated with superior LFS. Next-generation sequencing based on a myeloid gene panel was performed in 72 patients. Mutations in genes involved in cell signaling were associated with inferior LFS and OS, whereas those in genes involved in DNA methylation were associated with inferior LFS. KIT activation loop (AL) mutations occurred in 25 patients, and were associated with inferior LFS (P=0.003) and OS (P=0.001). TET2 mutations occurred in 8 patients, and were associated with significantly shorter LFS (P=0.015) but not OS. Patients negative for KIT-AL and TET2 mutations (N=41) had significantly better LFS (P<0.001) and OS (P=0.012) than those positive for both or either mutation. Multivariate analysis showed that KIT-AL and TET2 mutations were associated with inferior LFS, whereas age ⩾40 years and marrow blast ⩾70% were associated with inferior OS. These observations provide new insights that may guide better treatment for this AML subtype.
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: C Y
authors.initials: CY
authors.lastname: Cher
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: G M K
authors.initials: GM
authors.lastname: Leung
authors.affiliation: Department of Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, China.
authors.forename: C H
authors.initials: CH
authors.lastname: Au
authors.affiliation: Department of Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, China.
authors.forename: T L
authors.initials: TL
authors.lastname: Chan
authors.affiliation: Department of Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, China.
authors.forename: E S K
authors.initials: ES
authors.lastname: Ma
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: J P Y
authors.initials: JP
authors.lastname: Sim
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: H
authors.initials: H
authors.lastname: Gill
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: A K W
authors.initials: AK
authors.lastname: Lie
authors.affiliation: Department of Medicine, Hong Kong Sanatorium & Hospital, Hong Kong, China.
authors.forename: R
authors.initials: R
authors.lastname: Liang
authors.affiliation: Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: K F
authors.initials: KF
authors.lastname: Wong
authors.affiliation: Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: L L P
authors.initials: LL
authors.lastname: Siu
authors.affiliation: Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: C S P
authors.initials: CS
authors.lastname: Tsui
authors.affiliation: Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: C C
authors.initials: CC
authors.lastname: So
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: H W W
authors.initials: HW
authors.lastname: Wong
authors.affiliation: Department of Medicine, Tuen Mun Hospital, Hong Kong, China.
authors.forename: S F
authors.initials: SF
authors.lastname: Yip
authors.affiliation: Department of Medicine, Princess Margaret Hospital, Hong Kong, China.
authors.forename: H K K
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: H S Y
authors.initials: HS
authors.lastname: Liu
authors.affiliation: Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: J S M
authors.initials: JS
authors.lastname: Lau
authors.affiliation: Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China.
authors.forename: T H
authors.initials: TH
authors.lastname: Luk
authors.affiliation: Department of Medicine, Tseung Kwan O Hospital, Hong Kong, China.
authors.forename: C K
authors.initials: CK
authors.lastname: Lau
authors.affiliation: Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong, China.
authors.forename: S Y
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Y L
authors.initials: YL
authors.lastname: Kwong
authors.affiliation: Division of Haematology, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: A Y H
authors.initials: AY
authors.lastname: Leung
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003131:Combined Modality Therapy; D050660:Core Binding Factors / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D014178:Translocation, Genetic; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D050660:Core Binding Factors; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; D019009:Proto-Oncogene Proteins c-kit