Mosaad M El Gammal1, Gamal T Ebid2, Youssef M Madney3, Omnia M Abo-Elazm4, Ayda K Kelany5, Olga S Torra6, Jerald P Radich6. 1. Medical Oncology Department, National Cancer Institute, Cairo, Egypt. Electronic address: mosaad.elgammal@nci.cu.edu.eg. 2. Clinical Pathology Department, National Cancer Institute, Cairo, Egypt. 3. Pediatric Oncology, Cairo University and Children Cancer Hospital, Cairo, Egypt. 4. Cancer Epidemiology, Biostatistics Department, National Cancer Institute, Cairo, Egypt. 5. Genomic Medicine, Cairo University, Cairo, Egypt. 6. Fred Hutchinson Cancer Research Center, Seattle, WA.
Abstract
BACKGROUND: Genotypic mutation of fms like tyrosine kinase 3 (FLT3), Nucleophosmin (NPM1), and DNA-methyltransferase 3A (DNMT3A) has been involved in the leukemogenesis of acute myeloid leukemia (AML), with the well known poor prognostic role of FLT3 and DNMT3A and favorable role for the NPM1 mutation. PATIENTS AND METHODS: A total of 123 patients with AML treated at the National Cancer Institute, Cairo University were examined for mutations in DNMT3A, FLT3, and NPM1 using polymerase chain reaction (PCR) for detecting FLT3 internal tandem duplication (ITD) and allele-specific PCR to detect DNMT3A and NPM1A mutations. Two-way direct sequencing and Gene Mapper version 4.0 software (Fred Hutchinson Cancer Research Center) sequencing were used as confirmatory tests for DNMT3A and NPM1A mutations, respectively. RESULTS: DNMT3A, FLT3-ITD, and NPM1A gene mutations were detected in 22 (17.9%), 22 (17.9%), and 24 (19.5%) patients, respectively. DNMT3A/FLT3, NPM1A/FLT3, and DNMT3A/NPM1A combined mutant genotypes were detected in 5 (4.1%), 9 (7.3%), and 3 (2.4%) patients, respectively. Two patients (1.6%) had triple mutant genotypes (DNMT3A/FLT3/NPM1A). FLT3 and DNMT3A mutations had a significant negative effect on complete response (CR) rates (P = .016). FLT3-ITD mutation was significantly associated with older age (P = .029), and lower overall survival (OS) rates (P = .046). DNMT3A/FLT3 combined mutant genotypes were significantly associated with a lower OS rate (P = .016). Mutant NPM1/wild type FLT3, wild type DNMT3A/FLT3, and mutant NPM1A/wild type DNMT3A combinations were significantly associated with higher CR rates (P = .006, P = .006, and P = .023, respectively). CONCLUSION: DNMT3A, FLT3-ITD, and NPM1A are frequent mutations in Egyptian AML. FLT3-ITD mutations are frequent in older patients. DNMT3A and FLT3-ITD mutations were associated with an unfavorable prognosis, but the NPM1A mutation has tendency to indicate a good prognosis.
BACKGROUND: Genotypic mutation of fms like tyrosine kinase 3 (FLT3), Nucleophosmin (NPM1), and DNA-methyltransferase 3A (DNMT3A) has been involved in the leukemogenesis of acute myeloid leukemia (AML), with the well known poor prognostic role of FLT3 and DNMT3A and favorable role for the NPM1 mutation. PATIENTS AND METHODS: A total of 123 patients with AML treated at the National Cancer Institute, Cairo University were examined for mutations in DNMT3A, FLT3, and NPM1 using polymerase chain reaction (PCR) for detecting FLT3 internal tandem duplication (ITD) and allele-specific PCR to detect DNMT3A and NPM1A mutations. Two-way direct sequencing and Gene Mapper version 4.0 software (Fred Hutchinson Cancer Research Center) sequencing were used as confirmatory tests for DNMT3A and NPM1A mutations, respectively. RESULTS:DNMT3A, FLT3-ITD, and NPM1A gene mutations were detected in 22 (17.9%), 22 (17.9%), and 24 (19.5%) patients, respectively. DNMT3A/FLT3, NPM1A/FLT3, and DNMT3A/NPM1A combined mutant genotypes were detected in 5 (4.1%), 9 (7.3%), and 3 (2.4%) patients, respectively. Two patients (1.6%) had triple mutant genotypes (DNMT3A/FLT3/NPM1A). FLT3 and DNMT3A mutations had a significant negative effect on complete response (CR) rates (P = .016). FLT3-ITD mutation was significantly associated with older age (P = .029), and lower overall survival (OS) rates (P = .046). DNMT3A/FLT3 combined mutant genotypes were significantly associated with a lower OS rate (P = .016). Mutant NPM1/wild type FLT3, wild type DNMT3A/FLT3, and mutant NPM1A/wild type DNMT3A combinations were significantly associated with higher CR rates (P = .006, P = .006, and P = .023, respectively). CONCLUSION:DNMT3A, FLT3-ITD, and NPM1A are frequent mutations in Egyptian AML. FLT3-ITD mutations are frequent in older patients. DNMT3A and FLT3-ITD mutations were associated with an unfavorable prognosis, but the NPM1A mutation has tendency to indicate a good prognosis.