Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia

Norio Shiba, Kenichi Yoshida, Yuichi Shiraishi, Yusuke Okuno, Genki Yamato, Yusuke Hara, Yasunobu Nagata, Kenichi Chiba, Hiroko Tanaka, Kiminori Terui, Motohiro Kato, Myoung Ja Park, Kentaro Ohki, Akira Shimada, Junko Takita, Daisuke Tomizawa, Kazuko Kudo, Hirokazu Arakawa, Souichi Adachi, Takashi TagaAkio Tawa, Etsuro Ito, Keizo Horibe, Masashi Sanada, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi

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56 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)476-489
Number of pages14
JournalBritish Journal of Haematology
Issue number3
Publication statusPublished - 01-11-2016

All Science Journal Classification (ASJC) codes

  • Hematology


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