[Dynamic changes in genetic mutations in myelodysplastic neoplasms with progressive disease and leukemic transformation].

<b>Objective:</b> To investigate the key genetic mutations during the progressive disease (PD) /leukemic transformation (LT) course in MDS by analyzing the dynamic changes of genetic mutations in patients with myelodysplastic neoplasms (MDS) with or without PD/LT. <b>Methods:</b> This study enrolled 84 patients with sequential MDS from May 2019 to August 2023 at ZhongDa Hospital Southeast University and used the next generation sequencing to detect gene mutations. The dynamic changes of genetic mutations in patients with MDS with or without PD/LT were retrospectively analyzed. <b>Results:</b> ①This study analyzed data from 84 patients diagnosed with MDS with a median age of 63 (range: 31-95) years and consisting of 51 males and 33 females. Participants were distributed to the PD cohort (<i>n</i>=20), LT cohort (<i>n</i>=13), and non-PD/LT cohort (<i>n</i>=51). Patients from the PD/LT cohorts demonstrated a higher proportion of bone marrow blasts than the non-PD/LT cohort at the first sequencing (1.6% <i>vs</i>. 0.4%, <i>P</i>=0.013). ②The most frequently mutated genes that were detected at first sequencing were ASXL1 (<i>n</i>=21, 25.0%), TP53 (<i>n</i>=17, 20.2%), TET2 (<i>n</i>=12, 14.3%), DNMT3A (<i>n</i>=11, 13.1%), and U2AF1 (<i>n</i>=11, 13.1%). Further, patients from the PD/LT cohorts exhibited a higher median number of mutated genes than the non-PD/LT cohort (2 <i>vs</i>.1, <i>P</i>=0.014) at first sequencing. TET2 (27.3% <i>vs</i>. 5.9%, <i>P</i>=0.010), SETBP1 (15.2% <i>vs</i>.2.0%, <i>P</i>=0.033), and RUNX1 (18.2% <i>vs</i>. 2.0%, <i>P</i>=0.013) mutations were enriched in the PD/LT cohorts than in the non-PD/LT cohort. ③The most frequently detected acquired mutations (Ⅰ mutations) and clonally expanded mutations (Ⅱ mutations) were TP53 (<i>n</i>=9, 10.7%), TET2 (<i>n</i>=7, 8.3%), ASXL1 (<i>n</i>=7, 8.3%), and RAS pathway (<i>n</i>=7, 8.3%). Furthermore, patients from the PD/LT cohorts showed a higher median number of Ⅰ/Ⅱ genes than the non-PD/LT cohort (2 <i>vs</i>. 0, <i>P</i><0.001), and Ⅰ/Ⅱ RAS pathway (21.2% <i>vs</i>. 0, <i>P</i>=0.001), TP53 (27.3% <i>vs</i>. 0, <i>P</i><0.001), and TET2 (18.2% <i>vs</i>. 2.0%, <i>P</i>=0.013) mutations were enriched in PD/LT cohorts than in the non-PD/LT cohorts. ④Most of the TP53 mutations (9/12, 75.0%) in PD/LT cohorts were Ⅰ/Ⅱ mutations, whereas all of the TP53 mutations in non-PD/LT cohort were clone-decrease mutations (Ⅲ mutations) (5/8, 62.5%) or clone-stable mutations (Ⅳ mutations) (3/8, 37.5%). Most of the RAS pathway mutations (7/8,87.5%) in the PD/LT cohorts were Ⅰ/Ⅱ mutations, whereas only one patient in the non-PD/LT cohort demonstrated RAS pathway mutations, which belonged to Ⅳ mutations. <b>Conclusion:</b> Patients from the PD/LT cohorts demonstrated a higher proportion of bone marrow blasts and a higher median number of mutations than the non-PD/LT cohort at first sequencing; TET2, SETBP1, and RUNX1 mutations were enriched in the PD/LT cohorts than in the non-PD/LT cohort at first sequencing. Patients from the PD/LT cohorts exhibited a higher number of Ⅰ/Ⅱ mutations than the non-PD/LT cohort. Further, Ⅰ/Ⅱ TP53, RAS pathway, and TET2 mutations were enriched in the PD/LT cohorts, and Ⅰ/Ⅱ TP53 and RAS pathway mutations may contribute to the PD/LT.