2020
DOI: 10.3390/cancers12030637
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Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Abstract: 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)… Show more

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Cited by 54 publications
(50 citation statements)
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“…“Disruptive mutations” are categorized as DNA hot-spot aberrations that produce a STOP-sequence determining a desegregation of TP53 protein codification or DNA sequence alterations that arise inside the L2 or L3 binding domains (codons 163–195 or 236–251) and cause the substitution of an aminoacid with another of a different polarity/charge category. Conversely to what has been shown for solid tumors, discrimination into disruptive and non-disruptive TP53 mutations does not indicate a different outcome in patients with AML ( 69 ). The Evolutionary Trace (ET) method is an extensively standardized approach to assess key functional or structural residues in proteins ( 71 ).…”
Section: Functional Classification Of Tp53 Mutatiocontrasting
confidence: 71%
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“…“Disruptive mutations” are categorized as DNA hot-spot aberrations that produce a STOP-sequence determining a desegregation of TP53 protein codification or DNA sequence alterations that arise inside the L2 or L3 binding domains (codons 163–195 or 236–251) and cause the substitution of an aminoacid with another of a different polarity/charge category. Conversely to what has been shown for solid tumors, discrimination into disruptive and non-disruptive TP53 mutations does not indicate a different outcome in patients with AML ( 69 ). The Evolutionary Trace (ET) method is an extensively standardized approach to assess key functional or structural residues in proteins ( 71 ).…”
Section: Functional Classification Of Tp53 Mutatiocontrasting
confidence: 71%
“…It is not yet elucidated whether distinct types of TP53 mutations (non-sense, missense, deletions, insertions, slice site mutations) produce a uniformly dismal outcome in AML. Several studies have demonstrated that there are no differences in terms of OS and EFS between AML patients with missense TP53 mutations and those with truncating aberrations and that GOF activities elated for some missense TP53 variants do not represent the crucial mechanism of treatment resistance ( 66 69 ). A statistically significant impact on survival was identified between non-disruptive and disruptive TP53 mutations in a large study including patients with head and neck cancers ( 70 ).…”
Section: Functional Classification Of Tp53 Mutatiomentioning
confidence: 99%
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“…In AML, TP53 mutations have already been incorporated into current risk stratification guidelines and claims for a similar approach in MDS have been submitted (34,38). Using functional classification schemes, it has been shown that different TP53 mutations exert different prognostic impact in AML (42).…”
Section: Clinical Characteristics Of Patients With Aml and Mds With Tmentioning
confidence: 99%