Newly-Acquired and Clonally-Increased Mutations in TP53 and RAS Pathways Promote Progressive Disease and Leukemic Transformation in Patients with Myelodysplatic Neoplasms

Background Myelodysplastic neoplasms (MDS) are heterogeneous clonal hematopoietic neoplasms as progressive disease (PD) and leukemic transformation (LT) are involved with the accumulation of genetic abnormalities (Leukemia,2017,31:1928-1935). However, the relationship between PD/LT and the critical dynamic change in genetic mutations is not yet well defined. This study aimed to explore the key genetic mutations that may promote PD/LT in MDS patients. Methods 86 paired MDS patients were enrolled in the cohort, including 51 MDS with a low blast (MDS-LB),1 MDS with isolated 5q deletion (MDS-5q-), 6 MDS with low blasts and SF3B1 mutation (MDS-SF3B1),7 MDS with biallelic TP53 inactivation (MDS-biTP53), 2 MDS with fibrosis (MDS-f), 10 MDS with increased blasts type 1(MDS-IB1),8 MDS with increased blasts type 2 (MDS-IB2), from 30 May, 2019 to 16 August, 2023 at our institute. The patients were sequenced two times by our reported targeted exome-seq for 52 human leukemia driver genes (Blood Cancer J. 2022;12:145); The 1st sequencing was at diagnosis and the 2nd sequencing was at PD(20 patients), LT(13 patients), and non-PD/LT(51 patients), respectively. The mutations were defined into four groups based on the dynamic changes of variant allele frequency (VAF). If a mutation was not detected at 1st sequencing while detected at the 2nd sequencing, it was defined as a newly-acquired mutation. If the VAF of a mutation was increased by ≥10% in the 2nd sequencing versus the 1st sequencing, it was defined as a clonally-increased mutation. If the VAF of a mutation decreased by ≥10% in the 2nd sequencing versus the 1st sequencing, it was defined as a clonally-decreased mutation. If the VAF of a mutation changed ＜10% in the 2nd sequencing versus the 1st sequencing, it was defined as clone-stable mutations. Results The median number of genetic mutations in PD/LT cohorts was higher than non-PD/LT cohort (2 vs. 1, P=0.011) at diagnosis. Mutations in TET2 (25.7% vs.5.9%, P=0.012), RUNX1(17.1% vs.2%, P=0.017), and SETBP1(17.1% vs.2%, P=0.017) were more frequent in the PD/LT cohorts compared to the non-PD/LT cohort at diagnosis. The median number of newly-acquired and clonally-increased mutations in PD/LT cohorts was higher than in the non-PD/LT cohort(2 vs.0, P＜0.001). The newly-acquired and clonally-increased mutations inTP53 (25.7% vs.0%, P＜0.001), RAS pathway (22.9% vs.0%, P＜0.001), TET2(17.1% vs.2%, P=0.017) were more enriched in PD/LT cohorts compared to non-PD/LT cohort during the disease course, which suggested these mutations play a critical role in PD/LT. Most of the TP53 mutations (9/12,75%) were newly-acquired and clonally-increased mutations in the PD/LT cohorts; On the contrary, all of the TP53 mutations (8/8,100%) were clonally-decreased and clone-stable mutations in non-PD/LT cohorts. Then, we performed the co-mutation analysis with and without TP53 mutations in PD/LT patients, and the results showed that patients with TP53 mutations barely co-mutated with other clonally-decreased and clone-stable mutations. These results suggested that TP53 mutations are the direct factors for PD/LT. For patients without TP53 mutations, the most frequently co-clonally-decreased and co-clone-stable mutations were RAS pathway (6/26,23.1%), TET2 (5/26,19.2%), ASXL1 (4/26,15.4%), DDX41 (3/26,11.5%), and WT1 (3/26,11.5%) mutations. Similarly, in PD/LT cohorts, most of (8/9,88.8%) the RAS pathway mutations were newly-acquired and clonally-increased mutations, while in non-PD/LT cohorts, all of the RAS pathway mutations were clone-stable mutations. Conclusion The study clarified the dynamic changes of genetic mutation of MDS patients during the disease course. The increment of the newly acquired and clonally-increased mutations was associated with the PD/LT of MDS. Newly-acquired and clonally-increased TP53 and RAS pathway mutations may promote PD/LT in MDS patients, which may be potential targets as potential intervention points.