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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2019, Vol. 13 Issue (2) : 229-237    https://doi.org/10.1007/s11684-018-0616-1
RESEARCH ARTICLE
Mutation profiling of 16 candidate genes in de novo acute myeloid leukemia patients
Yang Zhang, Fang Wang, Xue Chen, Wenjing Liu, Jiancheng Fang, Mingyu Wang, Wen Teng, Panxiang Cao, Hongxing Liu()
Pathology & Laboratory Medicine Division, Hebei Yanda Lu Daopei Hospital, Langfang 065201, China
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Abstract

This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing. We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.
Keywords leukemia      myeloid      acute      gene      mutation     
Corresponding Author(s): Hongxing Liu   
Just Accepted Date: 04 April 2018   Online First Date: 29 May 2018    Issue Date: 28 March 2019
 Cite this article:   
Yang Zhang,Fang Wang,Xue Chen, et al. Mutation profiling of 16 candidate genes in de novo acute myeloid leukemia patients[J]. Front. Med., 2019, 13(2): 229-237.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0616-1
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I2/229
Fig.1  Mutation spectrum of 16 common mutated genes in AML. Rows in the graph represent individual gene mutations, and the columns represent individual patients in the study. Vertical blue lines indicate the presence of one mutation in a patient. Vertical yellow lines and red lines indicate the presence of double and triple mutations in a patient, respectively.
Fig.2  Gene function classification and co-occurrence of 16 common mutated genes in AML. (A) Co-occurrence of genes within three different function classifications. (B) Co-occurrence of signal transduction genes. (C) Co-occurrence of transcription factor genes. (D) Co-occurrence of epigenetic regulation genes.
FLT3-ITD M FLT3-ITD W P value NRAS M NRAS W P value KIT M KIT W P value
n = 42 n = 157 n = 38 n = 161 n = 28 n = 171
FLT3-ITD − − − 4(10.5%) 38(23.6%) * 1(3.6%) 41(24.0%) 0.014
CEBPA 5(11.9%) 34(21.7%) * 3(7.9%) 36(22.4%) 0.043 1(3.6%) 38(22.2%) 0.021
NRAS 4(9.5%) 34(21.7%) * − − − 2(7.1%) 36(21.1%) *
NPM1 14(33.3%) 21(13.4) 0.003 2(5.3%) 33(20.5%) 0.027 1(3.6%) 34(19.9%) *
KIT 1(2.4%) 27(17.2%) 0.014 2(5.3%) 26(16.1%) * − − −
PTPN11 1(2.4%) 17(10.8%) * 1(2.6%) 17(10.6%) * 0 18(10.5%) *
RUNX1 5(11.9%) 13(8.3%) * 3(7.9%) 15(9.3%) * 0 18(10.5%) *
DNMT3A 2(4.8%) 15(9.6%) * 2(5.3%) 15(9.3%) * 0 17(9.9%) *
IDH2 5(11.9%) 12(7.6%) * 2(5.3%) 15(9.3%) * 0 17(9.9%) *
TET2 2(4.8%) 14(8.9%) * 2(5.3%) 14(8.7%) * 0 16(9.4%) *
ASXL1 0 10(6.4%) * 2(5.3%) 8(5.0%) * 0 10(5.8%) *
FLT3-TKD 2(4.8%) 6(3.8%) * 1(2.6%) 7(4.3%) * 1(3.6%) 7(4.1%) *
KRAS 0 8(5.1%) * 1(2.6%) 7(4.3%) * 1(3.6%) 7(4.1%) *
ETV6 1(2.4%) 6(3.8%) * 0 7(4.3%) * 0 7(4.1%) *
IDH1 2(4.8%) 4(2.5%) * 0 6(3.7%) * 0 6(3.5%) *
PHF6 2(4.8%) 2(1.3%) * 0 4(2.5%) * 0 4(2.3%) *
TP53 0 4(2.5%) * 0 4(2.5%) * 0 4(2.3%) *
Tab.1  Co-occurrence of FLT3, NRAS, and KIT gene mutations
CEBPA M CEBPA W P value NPM1 M NPM1 W P value RUNX1 M RUNX1 W P value
n = 39 n = 160 n = 35 n = 164 n = 18 n = 181
FLT3-ITD 5(12.8%) 37(23.1%) * 14(40.0%) 28(17.1%) 0.003 5(2.8%) 42(23.2%) *
CEBPA − − − 2(5.7%) 37(22.6%) 0.023 0 39(21.5%) *
NRAS 3(7.7%) 35(21.9%) 0.043 2(5.7%) 36(22.0%) 0.027 3(16.7%) 38(21.0%) *
NPM1 2(5.1%) 33(20.6%) 0.023 − − − 1(5.6%) 34(18.8%) *
KIT 1(2.6%) 27(16.9%) 0.021 1(2.9%) 27(16.5%) * 0 28(15.5%) *
PTPN11 1(2.6%) 17(10.6%) * 5(14.3%) 13(7.9%) * 1(5.6%) 18(9.9%) *
RUNX1 0 18(11.3%) * 1(2.9%) 17(10.4%) * − − −
DNMT3A 1(2.6%) 16(10.0%) * 10(28.6%) 7(4.3%) 0.000 0 17(9.4%) *
IDH2 1(2.6%) 16(10.0%) * 8(22.9%) 9(5.5%) 0.003 0 17(9.4%) *
TET2 1(2.6%) 15(9.4%) * 6(17.1%) 10(6.1%) * 1(5.6%) 15(8.3%) *
ASXL1 0 10(6.3%) * 0 10(6.1%) * 3(16.7%) 7(3.9%) *
FLT3-TKD 0 8(5.0%) * 3(8.6%) 5(3.0%) * 0 8(4.4%) *
KRAS 0 8(5.0%) * 0 8(4.9%) * 1(5.6%) 8(4.4%) *
ETV6 1(2.6%) 6(3.8%) * 1(2.9%) 6(3.7%) * 0 7(3.9%) *
IDH1 1(2.6%) 5(3.1%) * 3(8.6%) 3(1.8%) * 0 6(3.3%) *
PHF6 0 4(2.5%) * 1(2.9%) 3(1.8%) * 1(5.6%) 3(1.7%) *
TP53 0 4(2.5%) * 0 4(2.4%) * 0 4(2.2%) *
Tab.2  Co-occurrence of CEBPA, NPM1, and RUNX1 gene mutations
DNMT3A M DNMT3A W P value IDH2 M IDH2 W P value TET2 M TET2 W P value
n = 17 n = 182 n = 17 n = 182 n = 16 n = 183
FLT3-ITD 2(11.8%) 40(22.0%) * 2(11.8%) 40(22.0%) * 2(12.5%) 40(21.9%) *
CEBPA 1(5.9%) 38(20.9%) * 1(5.9%) 38(20.9%) * 1(6.3%) 38(20.8%) *
NRAS 2(11.8%) 36(19.8%) * 2(11.8%) 36(19.8%) * 2(12.5%) 36(19.7%) *
NPM1 10(58.8%) 25(13.7%) 0.000 8(47.1%) 27(14.8%) 0.003 6(37.5%) 29(15.8%) *
KIT 0 28(15.4%) * 0 28(15.4%) * 0 28(15.3%) *
PTPN11 1(5.9%) 17(9.3%) * 1(5.9%) 17(9.3%) * 0 18(9.8%) *
RUNX1 0 18(9.9%) * 0 18(9.9%) * 1(6.3%) 17(9.3%) *
DNMT3A — — — 8(47.1%) 9(4.9%) 0.000 3(18.8%) 14(7.7%) *
IDH2 8(47.1%) 9(4.9%) 0.000 — — — 2(12.5%) 15(8.2%) *
TET2 3(17.6%) 13(7.1%) * 2(11.8%) 14(7.7%) * — — —
ASXL1 0 10(5.5%) * 0 10(5.5%) * 1(6.3%) 9(4.9%) *
FLT3-TKD 2(11.8%) 6(3.3%) * 0 8(4.4%) * 1(6.3%) 7(3.8%) *
KRAS 0 8(4.4%) * 0 8(4.4%) * 0 8(4.4%) *
ETV6 0 7(3.8%) * 0 7(3.8%) * 0 7(3.8%) *
IDH1 0 6(3.3%) * 0 6(3.3%) * 1(6.3%) 5(2.7%) *
PHF6 1(5.9%) 3(1.6%) * 0 4(2.2%) * 0 4(2.2%) *
TP53 0 4(2.2%) * 0 4(2.2%) * 1(6.3%) 3(1.6%) *
Tab.3  Co-occurrence of DNMT3A, IDH2, and TET2 gene mutations
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