| Myelodysplastic syndromes(MDS)is a group of chronic hematological malignancies characterized by cytopenia,hematopoietic failure,and high risk of progression to acute myeloid leukemia(AML).The pathogenesis of MDS may be closely related to solid tumors or exposure to adverse environment.The incidence of MDS is very low,according to the data registered by the American North American Cancer Registry and the American Center for Disease Control and Prevention,the average annual incidence of MDS in the United States is about 3.4/100,000 from 2001 to 2003.However,as the incidence of MDS is increasing in the elderly population,the incidence of MDS may increase with the arrival of the aging society.In addition,once the disease occurs,the disease progresses rapidly and the prognosis is poor.If being progressed in AML,patients’ survival time will be significantly shortened,so patients’survival and transformation outcomes are often the main outcomes of relevant studies.At the same time,the clinical characteristics of MDS patients are mainly manifested as varying degrees of hemocytopenia involving one or more lines and increase of bone marrow stem cells.These changes in blood and bone marrow characteristics affect the progression of the disease to some extent,which can be regarded as the secondary outcome of the disease.The clonal evolution hypothesis of leukemia suggests that the chimeric evolution of several genomic mutations in MDS patients leads to clonal diversity,and this clonal heterogeneity is generally composed of different subclones,among which the dominant subclones played an important driving role in disease progression.The rapid development of second-generation sequencing technology has made it possible to conduct large-scale parallel sequencing of multiple genes,and platforms are beginning to be used to analyze solid tumors and hematological malignancies.In this study,we analyzed the mutation expression of 23 genes in 231 patients with MDS using next-generation sequencing technology,and further explored the relationship between gene mutation and the changes of blood,marrow,survival outcomes and transformation outcomes by linear regression and Cox model,aiming to explain the role of gene mutation played in disease progression from a molecular perspective.It provides a theoretical basis for the targeted drug therapy sites of MDS patients,and also provides a supplement for the pathogenesis of the disease.Results:1.A total of 231 newly diagnosed MDS patients in Qilu Hospital from April 2016 to April 2020 were included in the study,of which 141 were male,and the proportion of female was 38.96%.The median age of incidence of the patients was 58 years old,and the age ranged from 15 to 86 years old.The median values of WBC,RBC,HGB,PLT,NEUT and RDW of the patients were significantly lower than the normal blood routine values under the routine tests,and the proportion of bone marrow stem cells was abnormally increased.2.Twenty-one of the 23 genes in targeted sequencing were mutated,among which the top five genes were:mutation rate of ASXL1was 21.64%,mutation rate of SF3B1 was 17.32%,mutation rate of U2AF1 was 16.02%,mutation rate of TET2 was 14.72%and mutation rate of TP53 was 8.66%,most of the mutations occurred in key gene domains.Common co-occurrence gene pairs mainly include ASXL1 and SETBP1,IDH1 and EZH2,ASXL1 and U2AF1.After the genes were classified according to the functional pathways,the mutation rate of RNA splicing gene groups(SF3B1,SRSF2,U2AF1,ZRSR2)was the highest,which was 39.83%.3.The differences of U2AF1 and TET2 gene mutations between genders were statistically significant,while the differences of SF3B1,U2AF1,TET2,TP53 and SRSF2 genes between age groups were statistically significant.4.After linear regression fitting with mutation status and mutations’VAF value as independent variables,ASXL1,NRAS,JAK2 and ZRSR2 gene mutations were positively correlated with the increase of RBC;NRAS and U2AF1 mutations were associated with changes in HGB.ETV6 mutation was associated with reduction of NEUT.SF3B1 and TET2 were correlated with the increase of MCV.JAK2,U2AF1,ASXL1 and SF3B1 were positively correlated with the increase of RDW.5.Mutations in RUNX1,IDH2,U2AF1 and NPM1 genes were associated with an increase of bone marrow stem cells.6.The median survival time of all follow-up patients was 25 months and the mortality rate was 39.83%.There were no differences in mortality rate between sex and age groups.There were no differences among different covariate groups.However,Cox model indicated that mutations of U2AF1,TP53 and DNMT3A genes were independent risk factors for the death of MDS patients.Compared with patients without mutation,the death risk of TP53 mutation was 2.486 times(1.256～4.919),U2AF1 mutation was 3.489 times(2.093～5.818),and DNMT3A mutation was 2.253 times(1.143～4.442).7.The median transformation time of all follow-up patients into AML within 3 years was 10 months,and the transformation rate was 16.45%.The transformation rate had statistically significant difference among different sex and treatment groups.Cox model suggested that ETV6 mutation was an independent risk factor for AML transformation in MDS patients,and the risk of ETV6 mutation was 6.731(1.356-33.414)times higher than that of nonmutation patients.Conclusion:1.Mutations of ASXL1,SF3B1,U2AF1,TET2 and TP53 genes were the most common mutated genes in MDS patients,while RNA splicing gene groups were the most common mutated gene groups.The mutated genes ASXL1 and SETBP1,IDH1 and EZH2,ASXL1 and U2AF1 showed the characteristics of co-mutation.2.Among 21 mutated genes,ASXL1,NRAS,JAK2,ZRSR2,U2AF1,SF3B1 and TET2 were most correlated with hemogram changes in MDS patients.Mutations in RUNX1,IDH2,U2AF1 and NPM1 genes were associated with increased bone marrow stem cells.3.Mutations of U2AF1,TP53 and DNMT3A genes were independent risk factors for the death of MDS patients.Research on targeted drugs for these genes may extend the life of patients.4.ETV6 gene mutation was an independent risk factor for the transformation of MDS patients to AML,suggesting that ETV6 gene mutation may occur early,and targeted therapy for patients with high frequency of ETV6 gene mutation may improve the prognosis of patients. |
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