TP53 mutation defines a unique subgroup within complex karyotype de novo and therapy-related MDS/AML

Abstract

A subset of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) show complex karyotype (CK), and these cases include a relatively high proportion of cases of therapy-related myeloid neoplasms and TP53 mutations. We aimed to evaluate the clinicopathologic features of outcome of 299 AML and MDS patients with CK. Mutations were present in 287 patients (96%) and the most common mutation detected was in TP53 gene (83%). A higher frequency of TP53 mutations was present in therapy-related cases (p=0.008) with a trend for worse overall survival (OS) in therapy-related patients as compared with de novo (p=0.08) and within the therapy-related group, the presence of TP53 mutation strongly predicted for worse outcome (p=0.0017). However, there was no difference in survival between CK patients based on categorization of AML versus MDS, (p=0.96) or presence of absence of circulating blasts ≥1% (p=0.52). TP53 mutated patients presented with older age (p=0.06) and lower hemoglobin (p=0.004) and marrow blast (p=0.02) compared to those with CK lacking TP53 mutation. Multivariable analysis identified presence of multi-hit TP53 mutation as strongest predictor of worse outcome, while neither a diagnosis of AML versus MDS nor therapy-relatedness independently influenced OS. Our findings suggest that among patients with MDS and AML, the presence of TP53 mutation (in particular multi-hit TP53 mutation) in the context of CK identifies a homogeneously aggressive disease, irrespective of the blast count at presentation or therapy-relatedness. The current classification of these cases into different disease categories artificially separates a single biologic disease entity.

Clinical Outcomes of Acute Myeloid Leukemia Patients Harboring the RUNX1 Mutation: Is It Still an Unfavorable Prognosis? A Cohort Study and Meta-Analysis

“…We hypothesize that our results might represent the sole impact of RUNX1 mut because less than 20% of the AML patients in our cohort had secondary AML, which was an independent risk factor for lower response rates, OS, and EFS [ 49 ]. Unlike AML with mutated TP53, which is a novel subtype with a homogeneously dismal prognosis, AML patients with RUNX1 mut seemed to have a heterogeneous prognosis, depending on the host and disease factors [ 50 , 51 , 52 , 53 , 54 , 55 ].…”

HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia

“…The published AML transcriptome datasets and the large number of AML immunohistochemical staining results demonstrate significantly higher HSF1 expression in different types of AML in general. It should be noted that TP53 is frequently mutated in AML with complex karyotype 83 , 84 , which may account for relatively higher HSF1 mRNA expression in AML with complex karyotype (Supplementary Fig. 4b, c ) given that wild type TP53 suppresses HSF1 expression and the mutant cancer genome 85 .…”

Molecular cytogenetics in acute myeloid leukemia in adult patients: practical implications

“…Most recurring chromosome alterations are unbalanced (monosomies, deletions, and unbalanced translocations) and result in loss of chromosome segments mainly from, in decreasing order, chromosome arms 5q, 17p, 7q, 18q, 16q, 17q, 12p, 20q, 18p, and 3p [70,[72][73][74][75]. Loss of 17p13 locus has been correlated with loss and mutations in the TP53 gene, and cause loss of p53 protein function that results in genetic instability and increased cell survival that contribute to pronounced genomic instability and poor outcome of patients with complex karyotype [76,77]. Gains of chromosomal material occur less often and are frequently hidden in unbalanced translocations and marker chromosomes.…”