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Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of...

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Autores principales: Dutta, Sayantanee, Pregartner, Gudrun, Rücker, Frank G., Heitzer, Ellen, Zebisch, Armin, Bullinger, Lars, Berghold, Andrea, Döhner, Konstanze, Sill, Heinz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139772/
https://www.ncbi.nlm.nih.gov/pubmed/32164171
http://dx.doi.org/10.3390/cancers12030637
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author Dutta, Sayantanee
Pregartner, Gudrun
Rücker, Frank G.
Heitzer, Ellen
Zebisch, Armin
Bullinger, Lars
Berghold, Andrea
Döhner, Konstanze
Sill, Heinz
author_facet Dutta, Sayantanee
Pregartner, Gudrun
Rücker, Frank G.
Heitzer, Ellen
Zebisch, Armin
Bullinger, Lars
Berghold, Andrea
Döhner, Konstanze
Sill, Heinz
author_sort Dutta, Sayantanee
collection PubMed
description Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15–4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06–3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making.
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spelling pubmed-71397722020-04-10 Functional Classification of TP53 Mutations in Acute Myeloid Leukemia Dutta, Sayantanee Pregartner, Gudrun Rücker, Frank G. Heitzer, Ellen Zebisch, Armin Bullinger, Lars Berghold, Andrea Döhner, Konstanze Sill, Heinz Cancers (Basel) Article Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15–4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06–3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making. MDPI 2020-03-10 /pmc/articles/PMC7139772/ /pubmed/32164171 http://dx.doi.org/10.3390/cancers12030637 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dutta, Sayantanee
Pregartner, Gudrun
Rücker, Frank G.
Heitzer, Ellen
Zebisch, Armin
Bullinger, Lars
Berghold, Andrea
Döhner, Konstanze
Sill, Heinz
Functional Classification of TP53 Mutations in Acute Myeloid Leukemia
title Functional Classification of TP53 Mutations in Acute Myeloid Leukemia
title_full Functional Classification of TP53 Mutations in Acute Myeloid Leukemia
title_fullStr Functional Classification of TP53 Mutations in Acute Myeloid Leukemia
title_full_unstemmed Functional Classification of TP53 Mutations in Acute Myeloid Leukemia
title_short Functional Classification of TP53 Mutations in Acute Myeloid Leukemia
title_sort functional classification of tp53 mutations in acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139772/
https://www.ncbi.nlm.nih.gov/pubmed/32164171
http://dx.doi.org/10.3390/cancers12030637
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