Analysis Of Clinical Characteristics Of U2AF1 Gene And Its Co-mutated Gene In 234 Patients With Myelodysplastic Syndrome

ObjectiveTo summarize the gene mutation and clinical characteristics of patients with myelodysplastic syndrome(MDS),to study the incidence,clinical characteristics and prognosis of mutant genes in patients with MDS,and to explore the clinical characteristics and prognostic value of mutation sites,mutation load and co-mutation of U2AF1 gene in patients with MDS.MethodsThe clinical data of 234 patients with MDS treated in the Department of Hematology of our hospital from January 2016 to January 2020 were collected retrospectively and followed up.The effects of 22 gene mutations on clinical characteristics,treatment efficacy and prognosis were analyzed.Results1.Among the 234 MDS patients,the total number of gene mutations was 347,and 72.2%of the patients had at least one gene mutation.Most of the MDS patients with 2 or more gene mutations were distributed in the extremely high-risk group of IPSS-R and the MDS-EB sub-type(P=0.022,P=0.024),and had increased risk of AML transformation(P=0.049).2.The mutant genes with higher incidence were TET2 mutation(32.9%),U2AF1 mutation(21.3%),ASXL1 mutation(16.6%),RUNX1 mutation(8.1%)and TP53 mutation(6.4%).Patients with TP53 mutation were more likely to be complicated with complex karyotype and chromosome 5 abnormalities.Patients with U2AF1 mutations were prone to chromosome 8 abnormalities,and chromosome 7 abnormalities were increased in patients with SETBP1 mutations.Patients in relapse group,AML progression group and non-ORR group after decitabine(DEC)treatment had higher RUNX1 variant allele frequency(VAP)values at diagnosis than those in non-recurrence group,non-progression group and ORR group,respectively(P=0.017,P=0.021,P=0.049).Patients with mutations of genes related to signal pathway were more likely to have abnormalities on chromosome 7(P=0.007),and comutation of RNA splice-related genes(r=0.183,P=0.005).The proportion of bone marrow blasts and the level of hemoglobin were higher in patients with epigenetic related gene mutations at diagnosis(P=0.028,P=0.007)3.The median VAF of U2AF1 gene mutations in 51 cases was 39.46%(1.38%-49.02%),all of them were heterozygous mutations,76.5%of U2AF1 mutations had co-mutations,and the protein sequences of U2AF1 gene mutations were S34F(32 cases),S34Y(11 cases),Q157P(7 cases),and 1 case was S34F and Q157P co-mutation.The patients with Q157P mutations had a higher incidence of abnormalities on chromosome 7(P=0.003),and were easy to be associated with signal pathway related gene mutations(NRAS,CBL,SETBP1,FLT3,etc.)(P=0.043).There was no significant difference in the mVAF,the response to DEC,the risk of recurrence and the risk of progression to AML among the three mutations.The patients with Q157P mutations had a poor prognosis(The median survival time of S34F?S34Y,Q157P:628d?804d and 184d,P=0.267),but the difference was not significant;Compared with the group with relatively low mutation load of U2AF1(VAF?40%),the group with relatively high mutation load of U2AF1(VAF>40%)had a higher incidence(P=0.045)and a significantly lower 1-year survival rate(41.3%and 76.9%,P=0.031),and response to DEC treatment was slightly worse,but the difference was not significant(ORR rates:25%and 25%,P=0.718).;Compared with U2AF1++ASXL1-patients,U2AF1++ASXL1+patients had a higher proportion of bone marrow primitive cells(P=0.05),a higher incidence of MDS-EB sub-type(P=0.047),and a higher risk of AML progression(P=0.012)?Compared with the U2AF1++TET2-group,the mutation load of U2AF1++TET2+group was lower(mVAF:35.5%and 48.2%,P=0.036),and the 1-year OS rate increased(1-year OS:66.7%and 54.5%,P=0.068).Compared with those with U2AF1++RUNX1-,those with U2AF1++RUNX1+had a higher risk of recurrence(P=0.028).4.After received 2-6 courses of DEC in 134 MDS patients,the overall response rate was 32.1%(43/134).There was no significant difference in the overall response rate between different DEC treatment doses and whether or not combined chemotherapy,Multivariate analysis shows that age and signaling pathways related genes mutation(NRAS,CBL,SETBP1,FLT3,etc.)are independent factors that affect the response of MDS patients to DEC treatment5.Multivariate analysis showed that VAF value exceeded 40%of U2AF1,chromosome 7 abnormality,EZH2 mutation,TP53 mutation and CBL mutation were independent adverse factors for the prognosis of MDS patients.6.RUNX1 mutation and SRSF2 mutation were independent factors that increased recurrence.In relapsed patients,a high proportion of primitive cells at initial diagnosis,and an independent factor of epigenetic related gene mutation(TET2,ASXL1,DNMT3A,etc.)to AML progression,the risk of AML progression was reduced by ORR after DEC treatment.Conclusion1.MDS patients with 2 or more mutated genes were mostly distributed in the IPSS-R high-risk group and the MDS-EB sub-type,and had a higher risk of AML progression.Those with a higher VAF value of RUNX1 at initial diagnosis suggested a high risk of recurrence,high risk of AML progression and poor response to DEC treatment.2.The mutated U2AF1 protein sequence may be correlated with chromosome abnormalities and co-mutated genes;Those with higher mutation load of U2AF1(VAF>40%)had poor prognosis.In addition,U2AP1 with ASXL1 mutation has a high risk of progression to AML,U2AF1 with RUNX1 mutation has an increased risk of recurrence,and U2AF1 with TET2 mutation may have a better prognosis.3.The VAF value exceeded 40%of U2AF1,EZH2 mutation,TP53 mutation and CBL mutation were independent adverse factors for prognosis.RUNX1 mutation and SRSF2 mutation were independent factors that increased the risk of recurrence.Epigenetic related gene mutations(TET2,ASXL1,DNMT3A,etc.)are independent factors affecting the progression of AML.Mutations in genes associated with the signaling pathway were independent factors(NRAS,CBL,SETBP1,FLT3,etc.)affecting the response to DEC therapy.