A Retrospective Study On Gene Mutation Spectrum In Patients With Myeloid Neoplasms

PART ?Objective:To describe the gene mutation spectrum in patients with acute myeloid leukemia(AML)and myelodysplastic syndrome with excess blasts(MDS-EB),and to explore the correlation between gene mutation and prognosis.Methods:The genes related to myeloid neoplasms in previous literature were searched,and the next generation sequencing profiles of a total of 45 genes were established,and the next generation sequencing of bone marrow or peripheral blood samples of patients with AML and MDS-EB was performed.Results:Of the 261 patients with AML,a total of 236 patients(90.4%)had mutationsdetected,involving 42 genes.The average number of mutations per patient was 2(range 0-8).The genes with the highest mutation frequency are CEBPA(16.0%,of which CEBPA biallelic 8.0%,CEBPA monoallelic 8.0%),followed by ASXL1(14.6%),NPM1(14.6%),FLT3-ITD(11.1%),DNMT3A(10.7%),IDH2(10.7%),NRAS(10.0%),TET2(9.6%),U2AF1(8.8%),PTPN11(8.4%),RUNX1(8.4%),IDH1(7.7%).After a median follow-up of 15 months,108 patients died.and the median overall survival was 17 months.The median overall survival of patients with mutations no less than 3 was shorter than that with mutations less than 3(P=0.020).The prognosis of AML patients with CEBPA biallelic mutation is better(P=0.016);TET2 mutant(P=0.007),U2AF1 mutant(P=0.038),TP53 mutant(P<0.001),SRSF2 mutant(P<0.001),SETBP1 mutant(P<0.001)AML patients have a worse prognosis.According to the 2017 European Leukemia Network(ELN)risk stratification standard,a total of 42 AML patients with chromosomal normal karyotypes in the intermediate-risk group were included,and a total of 36 patients(85.7?)had mutations detected,involving 28 genes.The average number of mutations per patient was 2(range 0-5).The genes with the highest mutation frequency were CEBPA monoallelic(21.4%)and DNMT3A(21.4%),followed by IDH2(19.0%),FLT3-ITD(11.9%),IDH1(11.9%),TET2(11.9%).After a median follow-up of 18 months,15 patients died,and the median overall survival was 22 months.The prognosis of AML patients with normal karyotype in the intermediate-risk group of CEBPA monoallelic was better(P=0.038).Compared with de novo AML patients,the mutation frequency of ASXL1,PTPN11,STAG2,EZH2,CALR gene is higher in patients with secondary acute myeloid leukemia.Of the 91 MDS-EB patients,78 patients(85.7%)detected at least one gene mutation,involving 35 genes.The average number of mutations per patient was 2(range 0-6).The genes with the highest mutation frequency were TP53(18.7%)and ASXL1(18.7%),followed by U2AF1(13.2%),RUNX1(12.1%),STAG2(12.1%),SF3B1(11.0%),SRSF2(11.0%).After a median follow-up of 10 months,8 people transformed to AML,and 39 patients died.The median overall survival was 14 months.The prognosis of MDS-EB patients with TP53 mutation(P<0.001)is worse.Compared with MDS-EB patients,NPM1,FLT3-ITD,NRAS,CEBPA biallelic,IDH1 gene mutation frequency is higher in AML patients;TP53,STAG2,SF3B1 gene mutation frequency is higher in MDS-EB patients.DNA methylation mutations and activated signal pathway mutations occur more frequently in AML patients than in MDS-EB patients;RNA splicing mutations occur more frequently in MDS-EB patients.Conclusion:Patients with AML and MDS-EB have molecular genetic heterogeneity.AML patients with normal karyotypes in the intermediate-risk group are a disease subgroup with strong molecular genetic heterogeneity;intermediate-risk normal karyotype AML patients with CEBPA monoallelic mutation may have a better prognosis.The gene mutation spectrum of patients with secondary acute myeloid leukemia is quite different from that of patients with de novo leukemia.PART ?Objective:To describe the gene mutation spectrum of patients with myelodysplastic syndrome with ring sideroblasts(MDS-RS),and to explore the difference of genetic mutation spectrum between SF3B1 mutant and SF3B1 wild-type patients.Methods:The next generation sequencing profiles of a total of 45 genes were established,and the next generation sequencing of bone marrow or peripheral blood samples of patients with MDS-RS was performed.Results:Of the 69 patients with MDS-RS,a total of 64 patients(92.8%)had gene mutation detected,involving 22 genes,and the average number of mutations per patient was 2(range 0-4).The gene with the highest mutation frequency was SF3B1(79.7%),followed by ASXL1(10.1%),DNMT3A(8.7%),and TET2(8.7%).SF3B1 gene mutations are all missense mutations and are in the HEAT domain.The most common mutation is K700E(60%).SF3B1 mutant and SF3B1 wild-type patients had no significant differences in age,sex,white blood cell level,hemoglobin level,platelet level,and the ratio of blast cells in bone marrow smears.After a median follow-up of 15 months,9 patients died,and the median overall survival has not yet been reached.There was no significant difference in overall survival between SF3B1 mutant and SF3B1 wild-type patients.Conclusion:SF3B1 mutation rate is high in patients with MDS-RS,mainly missense mutations,and the most common mutation is K700E.Whether SF3B1 mutant MDS-RS patients have independent clinical manifestations,cytogenetics,and gene mutation characteristics require larger studies.