Analysis Of Gene Mutations And Prognostic Factors In Rare Types Of Chronic Myeloid Neoplasms

A.ObjectiveThe analyze the clinical features,molecular genetic characteristics and the relationship between them in patients with rare types of chronic myeloid neoplasms,and their impact on prognosis.B.MethodsWe retrospectively analyzed the clinical features,gene mutation characteristics and prognostic factors of 83 patients with rare types of chronic myeloid neoplasms.All patients were treated at Qilu Hospital between December 12,2014 and October 27,2021,and all were diagnosed according to the WHO 2016 Classification.We analyzed the clinical features,gene mutation characteristics and discussed factors affecting patients’ survival.C.Resultsa.Clinical featuresAll patients had high white blood cell counts,neutrophil counts,and lactate dehydrogenase levels.Patients with CMML,aCML and MDS/MPN-U had both MDS and MPN clinical features,with CMML patients having higher monocyte counts,lower neutrophil counts and platelet counts,and aCML patients having higher percentage of peripheral blood blast cells.CNL and MPN-U had characteristics of MPN,with CNL patients having higher neutrophil counts and MPN-U patients having higher platelet counts and lower lymphocyte counts.54.2%of patients had combined hepatomegaly and/or splenomegaly at initial diagnosis,43.4%had combined constitutional symptoms,32.5%had transfusion dependence,and 30.7%had karyotype abnormalities.b.Genetic mutationsThere were multiple mutations in this group of patients with a high variant allele frequency(VAF)and co-mutations between different genes.The median number of mutations per patient was 2.0.Mutations were presented in 85.4%of patients,and the most frequent mutations were ASXL1,TET2,and SRSF2.CSF3R had a high mutation rate in CNL patients,and JAK2 had a high mutation rate in MPN-U patients.Mutations were also interrelated in this group of diseases,with coexisting mutations in ASXL1 and NRAS,U2AF1 and KRAS,DNMT3A and NPM1;and mutually exclusive mutations between ASXL1 and NPM1.These mutations are often involved in multiple pathways including signaling pathways,epigenetic regulation,splicing complex and transcriptional regulation.Among patients carrying mutations,the mutation frequency of signaling pathway-related genes reached 54.3%,with the highest mutation frequency of RAS signaling pathway-related genes,accounting for 52.6%of signaling pathway-related genes.By analyzing the VAF of high frequency mutations and exploring the possible order of mutation acquisition,it was found that TET2 and SRSF2 may be acquired at early disease stage,while ASXL1 and NRAS may have different acquisition order in different individuals.c.Analysis of the correlation between gene mutations and clinical featuresIn this study,we found that mutations in rare types of chronic myeloid neoplasms affect the clinical features of patients,with ASXL1 and TET2 mutations associated with age≥65 years and NRAS mutations associated with comorbid constitutional symptoms at initial diagnosis.In addition,the VAF value of the mutation also influenced the clinical features,and patients with high ASXL1 VAF were more likely to have splenomegaly at the initial diagnosis.d.Analysis of prognostic factorsGene mutations also affect the prognosis of patients with rare types of chronic myeloid neoplasms.The ASXL1 and TET2 mutations were independent prognostic risk factors,but no effect of high VAFs on disease prognosis was observed;in addition,patients with a platelet count≤100×109/L had a poor prognosis in clinical indicators.For patients in the CMML group in this study,age>70 years,platelet counts≤100×109/L,and ASXL1 mutation were independent prognostic risk factors.D.Conclusion1.CMML,CNL,aCML,MPN-U and MDS/MPN-U are a group of rare types of chronic myeloid neoplasms with an older age of onset,short median survival,and poor prognosis.Although there is significant heterogeneity in clinical features,they share a similar mutational profile and all involve signaling pathways,epigenetic regulation,splicing complex and transcriptional regulation.2.The clonal evolution pattern of this group of diseases was linear progression.TET2 and SRSF2 may be acquired at early disease stage,while ASXL1 and NRAS may have different acquisition order in different individuals.Some of the mutated genes were coexisting or mutually exclusive,with coexisting mutations between ASXL1 and NRAS,U2AF1 and KRAS,DNMT3A and NPM1;while mutually exclusive mutations existed between ASXL1 and NPM1.3.The type of gene mutation and the VAF value affect the clinical characteristics of the patient.ASXL1 and TET2 mutations associated with age≥65 years and NRAS mutations associated with comorbid constitutional symptoms at initial diagnosis.The patients with high ASXL1 VAF were more likely to have splenomegaly at the initial diagnosis,and ASXL1 mutations were significantly associated with karyotypic abnormalities.4.Platelet counts≤100×109/L,ASXL1 and TET2 mutation were independent poor prognostic factors for patients with rare types of chronic myeloid neoplasms in this study.Age≥70 years,platelet counts≤100×109/L and ASXL1 mutation were independent poor prognostic factors for patients with CMML in this study.