Oncotarget

Research Papers:

Mutational spectrum and risk stratification of intermediate-risk acute myeloid leukemia patients based on next-generation sequencing

Bianhong Wang, Yangyang Liu, Guangyuan Hou, Lili Wang, Na Lv, Yuanyuan Xu, Yihan Xu, Xiuli Wang, Zhaoling Xuan, Yu Jing, Honghua Li, Xiangshu Jin, Ailing Deng, Li Wang, Xiaoning Gao, Liping Dou, Junbin Liang, Chongjian Chen, Yonghui Li and Li Yu _

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Oncotarget. 2016; 7:32065-32078. https://doi.org/10.18632/oncotarget.7028

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Abstract

Bianhong Wang1,*, Yangyang Liu3,*, Guangyuan Hou3, Lili Wang2, Na Lv2, Yuanyuan Xu2, Yihan Xu2, Xiuli Wang3, Zhaoling Xuan3, Yu Jing2, Honghua Li2, Xiangshu Jin2, Ailing Deng2, Li Wang2, Xiaoning Gao2, Liping Dou2, Junbin Liang3,Chongjian Chen3,*, Yonghui Li2,*, Li Yu2,*

1Medical Center, Tsinghua University, Beijing 100084, China

2Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China

3Research and Development Department, Annoroad Gene Technology Co. Ltd, Beijing 100176, China

*These authors have contributed equally to this work

Correspondence to:

Li Yu, email: chunhuiliyu@yahoo.com

Yonghui Li, email: yonghuililab@163.com

Chongjian Chen, email: cchen@annoroad.com

Keywords: intermediate-risk acute myeloid leukemia, next generation sequencing, mutational screening and analysis, risk stratification

Received: June 29, 2015    Accepted: January 13, 2016    Published: January 27, 2016

ABSTRACT

Intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML cases, is highly heterogeneous. Although several mutations have been identified, the heterogeneity of AML is uncertain because novel mutations have yet to be discovered. Here we applied next generation sequencing (NGS) platform to screen mutational hotspots in 410 genes relevant to hematological malignancy. IR-AML samples (N=95) were sequenced by Illumina Hiseq and mutations in 101 genes were identified. Only seven genes (CEBPA, NPM1, DNMT3A, FLT3-ITD, NRAS, IDH2 and WT1) were mutated in more than 10% of patients. Genetic interaction analysis identified several cooperative and exclusive patterns of overlapping mutations. Mutational analysis indicated some correlation between genotype and phenotype. FLT3-ITD mutations were identified as independent factors of poor prognosis, while CEBPA mutations were independent favorable factors. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was identified with associated with specific clinical AML features and poor outcomes. Furthermore, by integrating multiple mutations in the survival analysis, 95 IR-AML patients could be stratified into three distinct risk groups allowing reductions in IR-AML by one-third. Our study offers deep insights into the molecular pathogenesis and biology of AML and indicated that the prognosis of IR-AML could be further stratified by different mutation combinations which may direct future treatment intervention.


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