TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseasesReport as inadecuate




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Journal of Hematology and Oncology

, 8:45

First Online: 08 May 2015Received: 18 February 2015Accepted: 20 April 2015DOI: 10.1186-s13045-015-0139-z

Cite this article as: Ok, C.Y., Patel, K.P., Garcia-Manero, G. et al. J Hematol Oncol 2015 8: 45. doi:10.1186-s13045-015-0139-z

Abstract

BackgroundTP53 mutation is more prevalent in therapy-related myeloid neoplasms t-MN than their de novo counterparts; however, the pattern of mutations involving TP53 gene in t-MN versus de novo diseases is largely unknown.

MethodsWe collected 108 consecutive patients with therapy-related myelodysplastic syndrome t-MDS-acute myeloid leukemia t-AML. Clinical, hematological, and cytogenetic data were collected by searching the electronic medical record. TP53 sequencing was performed in all patients using a clinically validated next-generation sequencing-based gene panel assay. A previously published patient cohort consisting of 428 patients with de novo MDS-AML was included for comparison.

ResultsWe assessed 108 patients with t-MN, in which 40 patients 37% had TP53 mutations. The mutation frequency was similar between t-MDS and t-AML; but significantly higher than de novo MDS-AML 62-428 patients, 14.5% p < 0.0001. TP53 mutations in t-MN were mainly clustered in DNA-binding domains, with an allelic frequency of 37.0% range, 7.1 to 98.8. Most mutations involved single nucleotide changes, of which, transitions 65.9% were more common than transversions 34.1%. Missense mutations were the most frequent, followed by frameshift and nonsense mutations. This TP53 mutation pattern was strikingly similar to that observed in de novo MDS-AML. TP53 mutations in t-MN were associated with a complex karyotype p < 0.0001, a higher number of chromosomal abnormalities p < 0.0001, and an inferior overall survival in affected patients 6.1 vs 14.1 months by univariate p < 0.0001 and multivariate analyses p = 0.0020.

ConclusionsOur findings support the recent notion that heterozygous TP53 mutation may be a function of normal aging and that mutated cells are subject to selection upon exposure to cytotoxic therapy. t-MN carrying TP53 mutation have an aggressive clinical course independent of other confounding factors.

KeywordsTP53 Therapy-related MDS AML Karyotype  Download fulltext PDF



Author: Chi Young Ok - Keyur P Patel - Guillermo Garcia-Manero - Mark J Routbort - Jie Peng - Guilin Tang - Maitrayee Goswami -

Source: https://link.springer.com/



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