FLT3-ITD, NPM1, and DNMT3A Gene Mutations and Risk Factors in Normal Karyotype Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients in Upper Northern Thailand

Abstract

Objective: Approximately 40-45% of AML and MDS patients have a cytogenetically normal karyotype (CN-AML and CN-MDS). The frequency and types of gene mutations in these cases may differ among various populations. The objective of this study was to identify frequencies and types of FLT3-ITD, NPM1, and DNMT3A mutations, and associations of them with clinical data and risk factors in CN-AML and CN-MDS cases in upper Northern Thailand. Methods: Bone marrow samples of 40 CN-AML and 60 CN-MDS patients were analyzed for gene mutations by direct sequencing. In addition, data for potential risk factors were obtained for comparison. Results: Frequencies of FLT3-ITD, NPM1, and DNMT3A mutations were 25.0%, 17.5%, and 10.0%, respectively in CN-AML, but all zero in CN-MDS cases. NPM1 mutations were found at a median age older than the wild type (58 vs 47 years) while DNMT3A mutations were associated with an increase in the white blood cell count. In all patients, factors for the mutations of these three genes included age ≤ 60 years, and a history of hypertension. Conclusion: When considering mutations in only normal karyotype patients, the frequency of FLT3-ITD, NPM1, DNMT3A mutations in CN-AML patients in upper Northern Thailand were found to occur at lower rates than in Western patients and to differ from other Asian populations including parts of Thailand. No mutations were observed in CN-MDS cases. Some types of gene mutations differed from previous studies, possibly attributable to differences in geography, lifestyle and genetic backgrounds. Links with age ≤ 60 years and history of hypertension were found. Investigation of these three genes in an intermediate risk group with a normal karyotype is useful for a better understanding of molecular leukemogenetic steps in CN-AML and CN-MDS patients and may be beneficial for planning treatment and prevention in the population of upper Northern Thailand.

Keywords: Cytogenetically normal; acute myeloid leukemia; myelodysplastic syndrome; upper Northern Thailand.

Figure 1

(A) Nucleotide Positions of Duplicated Sequence and Patterns of Mutations of FLT3-ITD, (B) Example of Pattern of Duplicated Sequences of Case 8

Figure 2

(A) Sequence Analysis of Nucleotide Positions and Patterns of NPM1 Mutations in Exon 12, (B) The Examples of Wild Type and C.863_864insCTCT Pattern of Reverse Sequences.

Figure 3

Sequence Analysis of Nucleotide Positions and Patterns of DNMT3A Mutations in Exon 23.