TP53 Gene allelic State in Myelodysplastic Syndromes (MDS) with Isolated 5q Deletion

Background & aim: The mutational status of TP53 gene is a significant prognostic factor in MDS, with two-thirds of patients harboring TP53 multihit alterations which are associated with poor outcomes. Approximately 20% of patients with MDS with isolated 5q deletion (MDS-del5q) exhibit TP53 aberrations, though their characteristics and prognostic impact have not been fully elucidated. In this study, we aimed to analyze the characteristics and impact of TP53 allelic state in patients with MDS-del5q. Methods: We conducted an international multicenter study in de novo MDS-del5q patients according to WHO 2017 classification. Clinical and biological characteristics, including the genetic profile were collected at diagnosis. Genetic profiling included conventional G-banding, TP53 deletion by FISH and/or SNP-arrays (for TP53 deletion and copy number neutral loss of heterozygosity). Also, the presence of mutations in myeloid-related genes was assessed by NGS or Sanger. Variant filtering and categorization were performed according to the Spanish Guidelines. Patients were classified as TP53 wild-type (TP53-wt), TP53-monoallelic, and TP53-multihit as proposed by Bernard et al. 2020. Clinical and molecular variables were evaluated for associations with acute myeloid leukemia (AML) evolution and overall survival (OS). In addition, a prognostic model to predict risk of AML evolution was developed using variables selected by the LASSO-cox method with minimum lambda. To calculate the points for each variable, a multivariate competitive risk model (Fine-Gray model) was fitted. Evolution to AML was used as the event and death as the competitive event. Statistical analysis was performed by R (4.2.2). Results: We included 682 patients with MDS-del5q (Table 1). Median follow-up was 66.8 months (CI95% 61.6-75.2). TP53 mutations were evaluated by NGS in 92.2% (n=629) and by Sanger in 7.8% (n=53) of patients. Overall, 18.7% (n=128) of MDS-del5q presented TP53 mutations. After integrating mutational data (FISH and SNP-arrays), 72.7% (n=93) of TP53-mutated patients were classified as TP53-monoallelic, whereas 27.3% (n=31) as TP53-multihit (4.5% of the whole cohort). Other recurrent mutations were SF3B1 (21%), DNMT3A (18%), TP53 (18%), TET2 (14%), ASXL1 (10%), CSNK1A1 (6%) and JAK2 (6%). Only bone marrow blasts differ between the TP53-wt and TP53-mutated groups ( p=0.031). Furthermore, only gender and VAF were different between TP53-monoallelic and TP53-multihit, being the number and