TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups

Abstract

Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of TP53 mutations, identified in 55% of patients. TP53 mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality ( p < 0.005), monosomal karyotype ( p < 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities ( p < 0.001). Monosomal karyotype, high complexity, and TP53 mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL ), NRAS mutation, SF3B1 mutation, TP53 mutation, elevated blast percentage (>10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse TP53 mutations and can be refined by considering clinical and karyotype features.

The impact of concomitant cytogenetic abnormalities on acute myeloid leukemia with monosomy 7 or deletion 7q after HLA‐matched allogeneic stem cell transplantation

“…Our hierarchical stratification may indeed reflect the increasing frequency of TP53 mutations across the groups as previously observed. 38,39 Our "abn(17p)" group translated into a 2-year probability of LFS of only 19% if transplanted in CR1, which is worse than previously published data. 18,40 These worse results might be related to the presence of 66% -5/5q-within the "abn(17p)" group, which supports our previous observation of the deleterious effect of the combination of -5/5q-and abn(17p) on outcomes after SCT.…”

“…If -7/7q-AML with or without CK demonstrated significant improved survival after SCT, the benefit of SCT is much more limited with the addition of MK, -5/5q-, abn(17p) and inv (3). Patients harboring MK, -5/5q-and abn (17p) have a high frequency of TP53 mutations, [36][37][38]51,52 which is known to be associated with chemo-resistance and lower sensitivity to a graft-vs-leukemia effect. 18 The first goal in those high-risk…”

“…15 20 (12-28) . 32 (29)(30)(31)(32)(33)(34)(35) 7q-vs -7 7q-44 (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49) .005 21 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26) .72 35 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) .004 42 (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)…”

The evolving role of next generation sequencing in myelodysplastic syndromes

“…TP53 acts as a transcription factor with pro‐apoptotic transcriptional targets (Lowe et al , ). Typically, TP53 mutations are LOF mutations that are phenocopied by del 17p; both of which are commonly associated with poor risk, complex karyotype, thrombocytopenia, elevated blasts and treatment‐related disease (Haase et al , ). Somatic TP53 mutations are commonly seen in MDS, but patients with Li‐Fraumeni syndrome, born with a single germline TP53 LOF mutation, are at an increased risk of developing MDS and AML, and other malignancies (Sperling et al , ).…”

Implications ofTP53Allelic State for Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes

“…TP53 is the most frequently mutated gene in cancer 1 , 2 . In patients with myelodysplastic syndromes (MDS), TP53 mutations have consistently been associated with high-risk disease features such as complex karyotype 3 , elevated blasts and severe thrombocytopenia 4 .…”