TP53 Mutation Status in Myelodysplastic Neoplasm and Acute Myeloid Leukemia: Impact of Reclassification Based on the 5th WHO and International Consensus Classification Criteria: A Korean Multicenter Study

Abstract

Background: TP53 mutations are associated with poor prognosis in myelodysplastic neoplasm (MDS) and AML. The updated 5th WHO classification and International Consensus Classification (ICC) categorize TP53-mutated MDS and AML as unique entities. We conducted a multicenter study in Korea to investigate the characteristics of TP53-mutated MDS and AML, focusing on diagnostic aspects based on updated classifications.

Methods: This study included patients aged ≥ 18 yrs who were diagnosed as having MDS (N=1,244) or AML (N=2,115) at six institutions. The results of bone marrow examination, cytogenetic studies, and targeted next-generation sequencing, including TP53, were collected and analyzed.

Results: TP53 mutations were detected in 9.3% and 9.2% of patients with MDS and AML, respectively. Missense mutation was the most common, with hotspot codons R248/R273/G245/Y220/R175/C238 accounting for 25.4% of TP53 mutations. Ten percent of patients had multiple TP53 mutations, and 78.4% had a complex karyotype. The median variant allele frequency (VAF) of TP53 mutations was 41.5%, with a notable difference according to the presence of a complex karyotype. According to the 5th WHO classification and ICC, the multi-hit TP53 mutation criteria were met in 58.6% and 75% of MDS patients, respectively, and the primary determinants were a TP53 VAF >50% for the 5th WHO classification and the presence of a complex karyotype for the ICC.

Conclusions: Collectively, we elucidated the molecular genetic characteristics of patients with TP53-mutated MDS and AML, highlighting key factors in applying TP53 mutation-related criteria in updated classifications, which will aid in establishing diagnostic strategies.

Keywords: Acute myeloid leukemia; International Consensus Classification; Myelodysplastic syndromes; TP53 mutation; World Health Organization.

Fig. 1. Characteristics of TP53 mutations in patients with MDS or AML. (A) Spectrum of TP53 mutations (numbers in circular discs are the numbers of TP53 mutations identified). (B) Types of TP53 mutations. (C) Distribution of the TP53 mutation VAF according to disease categories, presence of 17p loss, and a CK. (D) Proportions of 17p loss and a CK based on a 50% VAF threshold. (E) Status of 17p loss and CK according to the number of TP53 mutations.

Abbreviations: MDS, myelodysplastic neoplasm; VAF, variant allele frequency; CK, complex karyotype; ND, not determined.

Fig. 2. Mutation heatmap of patients with MDS and AML with TP53 mutations.

*These include cytogenetic abnormalities that are neither normal nor complex karyotypes (defined as having three or more abnormalities). Abbreviations: MDS, myelodysplastic neoplasm; ICC, International Consensus Classification; AML-recurrent, AML with recurrent genetic abnormalities; AML-MRC, AML with myelodysplasia-related changes; AML-NOS, AML, not otherwise specified; MDS-NEB, MDS with non-excess blasts; MDS with EB1, MDS with excess blasts 1; MDS with EB2, MDS with excess blasts 2; NK, normal karyotype; CK, complex karyotype; N, no; Y, yes.