DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications

• Published in: Blood Vol. 119; no. 2; pp. 559 - 568
• Main Authors: Hou, Hsin-An, Kuo, Yuan-Yeh, Liu, Chieh-Yu, Chou, Wen-Chien, Lee, Ming Cheng, Chen, Chien-Yuan, Lin, Liang-In, Tseng, Mei-Hsuan, Huang, Chi-Fei, Chiang, Ying-Chieh, Lee, Fen-Yu, Liu, Ming-Chih, Liu, Chia-Wen, Tang, Jih-Luh, Yao, Ming, Huang, Shang-Yi, Ko, Bor-Sheng, Hsu, Szu-Chun, Wu, Shang-Ju, Tsay, Woei, Chen, Yao-Chang, Tien, Hwei-Fang
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 12.01.2012; Americain Society of Hematology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Chromosome Aberrations; Disease Progression; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Mutational Analysis; Female; Hematologic and hematopoietic diseases; Humans; Karyotyping; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Mutation - genetics; Polymerase Chain Reaction; Prognosis; Remission Induction; Survival Rate; Young Adult; Acute myelogenous leukemia; Stability; Hematology; Evolution; Genetics; Malignant hemopathy; Mutation; Cancer
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-369934

DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P < .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease.