title: Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia.
abstract: Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole-exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence.
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.|Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shiba
authors.affiliation: Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.|Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Genki
authors.initials: G
authors.lastname: Yamato
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.|Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Paediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Terui
authors.affiliation: Department of Paediatrics Haematology and Oncology Research, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.
authors.forename: Myoung-Ja
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of Paediatrics Haematology and Oncology Research, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Department of Paediatrics, Okayama University Graduate School of Medicine, Okayama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.affiliation: Department of Paediatrics, The University of Tokyo, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.affiliation: Division of Leukaemia and Lymphoma, Children's Cancer Centre, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomizawa
authors.affiliation: Department of Paediatrics, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kudo
authors.affiliation: Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Arakawa
authors.affiliation: Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.affiliation: Department of Paediatrics, Shiga University of Medical Science, Ohtsu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Taga
authors.affiliation: Department of Paediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Tawa
authors.affiliation: Department of Paediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ito
authors.affiliation: Clinical Research Centre, National Hospital Organization Nagoya Medical Centre, Nagoya, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Horibe
authors.affiliation: Clinical Research Centre, National Hospital Organization Nagoya Medical Centre, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Sequence Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan. hayashiy-tky@umin.ac.jp.|Japanese Red Cross Gunma Blood Centre, Maebashi, Japan. hayashiy-tky@umin.ac.jp.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D002648:Child; D060965:Clonal Evolution / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D044127:Epigenesis, Genetic; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D008297:Male; D009154:Mutation; D000090243:Nucleophosmin; D011379:Prognosis; D012008:Recurrence
keywords: 
  ASXL2
  ; 
  BCORL1
  ; cohesin; paediatric acute myeloid leukaemia; whole-exome sequencing