Myelodysplastic syndrome (MDS) is an hematopoietic stem cells (HSCs) disorder, leading to malignant cells that ultimately grow uncontrollably. Somatic mutations of spliceosomal gene such as SF3B1, U2AF1 and SRSF2 has been widely described in MDS and other hematological malignancies. Many reports state that hematopoietic malignancies mostly result from somatic mutations in HSCs in the bone marrow. Some functional studies have been performed and have shown that a high proportion of these cases are associated with somatic mutations in spliceosomal proteins. Also, such kinds of mutation are hallmarks of dominantly acting and growing specific cancer. Many efforts have been made to unravel the mutation considered disease background of MDS. Genotype–phenotype associations have been demonstrated for somatic spliceosomal gene mutation in MDS with ring sideroblasts but there is not much research regarding aberrant splicing pathways in MDS without harboring ring sideroblast. Therefore, this study investigated the prevalence and prognostic implication of the SF3B1, U2AF1 and SRSF2 splice gene mutation in these patients in Korea.
The study cohort of 92 MDS patients was examined for somatic mutations in SF3B1, U2AF1 and SRSF2 splicing gene using direct sequencing method. The clinical and hematologic data were also recorded. The collected data was analyzed by SPSS for Windows version 18. 0. Pearson's chi-square tests, one way ANOVA analysis, and Student t-test were performed. Survival rates of multiple myeloma patients according to the mutation result of SF3B1, U2AF1 and SRSF2 splicing gene were analyzed using Kaplan-Meier log-rank test.
Our 92 MDS patients showed recurrent mutation and polymorphisms. Mutations in K666N, H662Q and K700E of SF3B1; S34T, S34P and Q157P of U2AF1; P95H, P95R and P95L of SRSF2 were found in 8 (8. 7%), 6 (6. 5%), and 11 (11. 9%) patients, respectively. The patients displayed 39198T>T/C polymorphism (88. 0%) in exon 18 of SF3B1, 8345T>T/G polymorphism (7. 6%) in exon 2 of U2AF1 and 5399C/T polymorphism (100%) in exon 1 of SRSF2. In the entire cohort, the number of patients with no polymorphism, one polymorphism, two polymorphisms and three polymorphisms was counted up to 0%, 12%, 80. 4% and 7. 6%, respectively. The T/C polymorphism at position 39198 of SF3B1 exon 18 and the T/G polymorphism at position 8345 of U2AF1 exon 2 were analyzed by allele-specific PCR using normal control. Results in 100 normal controls, polymorphism of SF3B1 exon 18 was taken into account of 82. 0%, the remaining is non polymorphism while U2AF1 exon 2 showed 10. 0% polymorphism and 90. 0% non polymorphism. The patient with either polymorphisms or mutations in both SF3B1, U2AF1 and SRSF2 had no effect on overall survival and disease-free survival.
Our results show that mutation rate of SF3B1, U2AF1 and SRSF2 splice gene in Korean MDS patients without harboring ring sideroblast displayed relatively rare and infrequent molecular event. Moreover, alteration of SF3B1, U2AF1 and SRSF2 splice gene was not significantly implicated in the clinical outcomes and prognosis.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.