| BackgroundAcute myeloid leukemia (AML) is a malignant clonal disease in hematopoietic system caused by karyotype mutation in pluripotent stem cells or mildly differentiated precursor cells. AML include all sources of acute non-lymphocytic leukemia. Some types of AML have low survival and high recurrence rate. However, the prognostic factors remain unknown for these subtypes.ObjectiveThe study was performed to systemically investigate the frequencies of molecular mutations in AML patients and to evaluate the prognostic value of genetic mutations.MethodsA total of 1,185 primary AML patients diagnosed between 1998 and 2011 were collected from Shanghai Institute of Hematology and Zhejiang Institute of Hematology. After excluding those with mutations at AML1-ETO, CBF-MYH1 and PML-RARa/NPM1-RARa genes,605 patients were included in this study. All patients had chemotherapy with daunorubicin and cytarabine (DA program). Only 47 patients were transplanted with marrow from suitable donors. Through reviewing medical records, we obtained clinical information for all patients, including sex, age, white blood cell (WBC) counts (×109/L), blasts in bone marrow (BM) (%) and FAB types and complete remission (CR) status after the first chemotherapy. The effect of chemotherapy was determined according to the patients’symptoms, signs, and results of blood and bone marrow smears. Bone marrow karyotype analysis was conducted by R-banding or G-banding methods and confirmed with related molecular markers. Mutations at genes of FLT3-TKD, N-RAS, NPM1 and IDH1 were examined using chip-based matrix-assisted laser absorption/ionization mass spectroscopy, whereas mutations at genes of FLT3-ITD, c-KIT, CEPBA and DNMT3A were detected by whole genome sequencing methods. Mutations at MLL-PTD gene and six MLL-related fusion genes, i.e. MLL-AF9, MLL-AF10, MLL-AF6, MLL-ELL, MLL-ENL and MLL-AF17 genes were identified using multiplex RT-PCR. The status of gene mutation was recorded as with or without mutations. All patients were followed-up to collect information on survival status and causes of death by the end of 2012.ResultsA significant difference was observed in the medians of WBC counts and BM blasts between AML patients with and without mutation at FLT3-ITD/TKD, NPM or DNMT3A genes (all P values for t tests< 0.05). The CR rates after chemotherapy differed significantly between patients having and having no mutation at MLL/PKD, NPM, NRAS or CEBPA genes (all P values for Fisher X2 tests< 0.05). The median survival time were 8.0 ± 2.2 weeks and 7.0 ±2.1 weeks, respectively, in patients with MLL/PKD mutation or DNMT3A mutation, significantly higher than 17.0 ± 2.4 weeks and 18.0 ± 2.3 weeks among those without mutation. After adjusting for age, sex, WBC counts, BM blasts and FAB type, the hazard ratio (HR) and 95% confidence interval was 1.9 (95%CI:1.3-2.7) for patients with vs. without mutation at MLL/PKD gene and 1.6 (95%CI:1.1-2.4) for those with vs. without mutation at DNMT3A gene. Conversely, mutations at NPM and CEBPA were associated with a favorable prognosis, with HR being 0.6 (95%CI:0.4-0.9) and 0.6 (95%CI:0.5-0.9), respectively. The risk was observed to increase with the increasing number of risk mutations at the four genes (P for trend< 0.0001).Conclusion:Our results suggest that genetic mutation assay may be helpful for selecting an efficient chemotherapy and predicting the prognosis among Chinese AML patients. |
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