Format

Send to

Choose Destination
Br J Haematol. 2016 Nov;175(3):476-489. doi: 10.1111/bjh.14247. Epub 2016 Jul 29.

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

Author information

1
Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan.
2
Department of Paediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan.
3
Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
4
Laboratory of DNA Information Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5
Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
6
Laboratory of Sequence Analysis, Human Genome Centre, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
7
Department of Paediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
8
Department of Paediatrics Haematology and Oncology Research, National Centre for Child Health and Development, Tokyo, Japan.
9
Department of Paediatrics, Okayama University Graduate School of Medicine, Okayama, Japan.
10
Department of Paediatrics, The University of Tokyo, Tokyo, Japan.
11
Division of Leukaemia and Lymphoma, Children's Cancer Centre, National Centre for Child Health and Development, Tokyo, Japan.
12
Department of Paediatrics, Fujita Health University School of Medicine, Toyoake, Japan.
13
Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
14
Department of Paediatrics, Shiga University of Medical Science, Ohtsu, Japan.
15
Department of Paediatrics, National Hospital Organization Osaka National Hospital, Osaka, Japan.
16
Clinical Research Centre, National Hospital Organization Nagoya Medical Centre, Nagoya, Japan.
17
Department of Haematology/Oncology, Gunma Children's Medical Centre, Shibukawa, Japan. hayashiy-tky@umin.ac.jp.
18
Japanese Red Cross Gunma Blood Centre, Maebashi, Japan. hayashiy-tky@umin.ac.jp.

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.

KEYWORDS:

ASXL2 ; BCORL1 ; cohesin; paediatric acute myeloid leukaemia; whole-exome sequencing

PMID:
27470916
DOI:
10.1111/bjh.14247
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center