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Whole‐exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia
Author(s) -
Shiba Norio,
Yoshida Kenichi,
Shiraishi Yuichi,
Okuno Yusuke,
Yamato Genki,
Hara Yusuke,
Nagata Yasunobu,
Chiba Kenichi,
Tanaka Hiroko,
Terui Kiminori,
Kato Motohiro,
Park Myoungja,
Ohki Kentaro,
Shimada Akira,
Takita Junko,
Tomizawa Daisuke,
Kudo Kazuko,
Arakawa Hirokazu,
Adachi Souichi,
Taga Takashi,
Tawa Akio,
Ito Etsuro,
Horibe Keizo,
Sanada Masashi,
Miyano Satoru,
Ogawa Seishi,
Hayashi Yasuhide
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14247
Subject(s) - cebpa , exome sequencing , npm1 , biology , massive parallel sequencing , myeloid leukaemia , mutation , exome , epigenetics , myeloid , gene , genetics , cancer research , dna sequencing , karyotype , chromosome
Summary 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 , NPM 1 , CEBPA and FLT 3 in both adult and paediatric AML . In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH 1/2 and DNMT 3A ) in adult AML . In this study, whole‐exome sequencing ( WES ) of 22 paediatric AML patients revealed mutations in components of the cohesin complex ( RAD 21 and SMC 3 ), BCORL 1 and ASXL 2 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 [ STAG 2 , RAD 21 and SMC 3 in 17 patients (8·3%)], epigenetic regulators [ ASXL 1/ ASXL 2 in 17 patients (8·3%), BCOR / BCORL 1 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.