Introduction
TP53 mutations (TP53MT) are seen in ~10% of myelodysplastic syndromes (MDS). TP53MT are distributed across the entire coding region, with less than a third occurring in focal hotspots. In vitro and in silico studies suggest that different types of TP53MT lead to distinct functional consequences that include oncogenic gain-of-function and protein loss-of-function with dominant-negative effect. The functional effects of these mutations likely influence disease biology and outcome, either independently or by influencing known variables such as VAF and karyotype. While studies have shown that TP53MT MDS with complex/monosomal karyotype (CK/MK) and multiallelic TP53 alterations have a worse prognosis, however, the impact of different types of TP53MT on phenotype, prognosis and outcome of MDS is not known. To assess this, we quantified the deleterious effects of missense TP53MT using the computationally-derived evolutionary action score (EAp53, range, 0-100, higher score indicates worse impact), followed by 3D protein mapping to identify prognostic subsets.
Methods
We selected 270 consecutive newly-diagnosed MDS and oligoblastic AML with at least 1 missense TP53MT by NGS. EA53 scores were determined using evolutionary trace approach. TP53 immunohistochemistry (IHC) was performed on selected cases. The optimal EAp53 cutoff was determined using recursive partitioning and regression trees (RPART) based on Classification & Regression Trees. TP53 protein structural analysis was conducted using the PyMOL molecular visualization system and the crystal structure of the TP53 core domain in complex with DNA (PDB ID of 4HJE).
Results
The median age was 68 (18-90)]. Majority (81%) had a CK. The median EAp53 score was 79 (4-98) [Fig 1A, 1B]. Using RPART, we identified an EAp53 score >52 predicted for worse OS (median, 10 vs. 48 months; HR: 2.6 [1.22-5.56]; p=0.01) [Fig 1C]. We divided our cohort into low-EAp53 (≤52; n=17, 6%) and high-EAp53 (n=253, 94%). Low-EA MDS had fewer cytogenetic abnormalities [median, 3 vs. 7; p=0.019], lower frequency of CK/MK (p=0.02), lower number of additional TP53MT (6% vs. 32%, p=0.027), lower frequency of multiallelic TP53 alterations (29% vs. 63%, p=0.009), and higher number of additional gene mutations (63% vs. 33%; p=0.05) involving NRAS and RUNX1 genes (p=0.02). There was no difference in median TP53 VAF or R-IPSS scores (Table 1). By TP53 immunohistochemistry, TP53 protein expression was significantly different between wild-type (median H-score, 6), low EAp53 (48) and high EAp53 (158) [wild-type vs. low EA, p=0.04; low vs. high EA, p=0.0014]. Low EAp53 showed clearance of TP53 mutation in 67% (vs. 45%) in those that achieved partial/ complete response.
Due to observed differences in outcome despite similar EAp53 score, we correlated survival with the mutant location within 3D protein structure. Majority of mutations mapped to the evolutionarily important sites of the TP53 core domain, residues near the DNA binding site or within the protein structural core and solvent inaccessible (Fig 1D). We divided our cohort into two groups based on a survival cut-off of 10 months. TP53MT associated with OS <10 months formed two clusters: a large cluster interfacing with the DNA binding site and a small cluster formed by residues V157, Y220, L257 and E258 (Fig 1E).
By univariate analysis, the following associated with worse OS: higher TP53 VAF (as a continuous variable), higher number of TP53MT, high-risk EAp53 (>52) group, higher IPSS-R score, presence of CK/MK, higher serum LDH and creatinine levels, lower platelet, hemoglobin, and serum albumin. TP53 allele state and del(17p) did not associate with OS. By multivariable analysis (CK excluded due to due to a strong association with EAp53), high-EAp53 was associated with worse OS independent of R-IPSS score [HR 5.1; CI 1.5-17.2; p=0.009]. Neither TP53 VAF nor the number of TP53MT was independently prognostic.
Conclusions
A subset of TP53MT MDS patients with low-EAp53 (≤52) showed improved outcomes independent of TP53 VAF or IPSS-R scores in HMA treated MDS, and associated with specific clinico-pathologic features. High-EAp53 associated with worse OS independent of R-IPSS score. Mutational mapping using 3D protein model showed clustering of poor-outcome mutations, suggesting that structural location further influences the outcome. Combination of EAp53 and 3D mapping can be help identify prognostic subsets.
Sasaki:Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Honoraria. Jabbour:AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding. Kadia:Celgene: Research Funding; Cyclacel: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Ascentage: Research Funding; JAZZ: Honoraria, Research Funding; Incyte: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Astra Zeneca: Research Funding. Andreeff:Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Honoraria. Daver:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Kantarjian:Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Aptitute Health: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Oxford Biomedical: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding. Garcia-Manero:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Novartis: Research Funding; Onconova: Research Funding.
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