title: Mutational spectrum and risk stratification of intermediate-risk acute myeloid leukemia patients based on next-generation sequencing.
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.
authors.affiliation: Medical Center, Tsinghua University, Beijing 100084, China.
authors.forename: Bianhong
authors.initials: B
authors.lastname: Wang
authors.affiliation: Research and Development Department, Annoroad Gene Technology Co. Ltd, Beijing 100176, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Research and Development Department, Annoroad Gene Technology Co. Ltd, Beijing 100176, China.
authors.forename: Guangyuan
authors.initials: G
authors.lastname: Hou
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Na
authors.initials: N
authors.lastname: Lv
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Research and Development Department, Annoroad Gene Technology Co. Ltd, Beijing 100176, China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Research and Development Department, Annoroad Gene Technology Co. Ltd, Beijing 100176, China.
authors.forename: Zhaoling
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Ailing
authors.initials: A
authors.lastname: Deng
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Dou
authors.affiliation: Research and Development Department, Annoroad Gene Technology Co. Ltd, Beijing 100176, China.
authors.forename: Junbin
authors.initials: J
authors.lastname: Liang
authors.affiliation: Research and Development Department, Annoroad Gene Technology Co. Ltd, Beijing 100176, China.
authors.forename: Chongjian
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D050939:Gene Fusion; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020014:K562 Cells; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D000090243:Nucleophosmin
keywords: intermediate-risk acute myeloid leukemia; mutational screening and analysis; next generation sequencing; risk stratification