Alteration of SF3B1 and SRSF2 Genes in Myelodysplastic Syndromes Patients in Upper Northern Thailand

Background: The frequency and pattern of mutation in SF3B1 and SRSF2 RNA splicing machinery genes were found to vary among myelodysplastic syndrome (MDS) patients in different populations. There have been less reports of incidence of these gene mutations in Thailand especially in upper northern Thailand. This study therefore had aims to investigate the frequency and pattern of mutation in mutational hotspot of SF3B1 and SRSF2 genes among MDS patients in upper northern Thailand and to investigate the clinical features associated with the mutations. Methods: Fifty-five MDS patients who underwent treatment at Maharaj Nakorn Chiang Mai Hospital participated in this study. The detection of SF3B1 and SRSF2 hotspot mutations was carried out using polymerase chain reaction followed by Sanger sequencing. In addition, clinical features of individual patients with these gene mutations were also investigated. Results: SF3B1 mutations (SF3B1mut) were found in 9 patients (16.4%) including E622D (1/9), R625C (1/9), H662Q (1/9), K700E (5/9), and Q699H co-mutation with K700E (1/9). SRSF2 mutations (SRSF2mut) were found in 4 patients (7.3%) which included P95H (3/4) and P95L (1/4). The SF3B1mut was associated with lower hemoglobin levels (p = 0.023) and higher platelet counts (p = 0.047) when compared with MDS patients without SF3B1mut, while SRSF2mut tended to occur in patients with a higher percentage of bone marrow blasts (p = 0.074). Conclusion: The findings confirmed the difference in frequency of SF3B1 and SRSF2 mutations among different populations. Specifically, we found a co-mutation of Q699H and K700E that has not been previously reported in MDS patients in the COSMIC database. It was also found that SF3B1mut was strongly associated with low hemoglobin level, and high platelet counts whereas SRSF2mut was mostly clustered in MDS with excess blasts subsequently increasing the probability of progression to acute myeloid leukemia.

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

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.