Top

Published in:

Open Access 01-12-2021 | Myelodysplastic Syndrome | Research

TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

Authors: Pimjai Niparuck, Pornnapa Police, Phichchapha Noikongdee, Kanchana Siriputtanapong, Nittaya Limsuwanachot, Budsaba Rerkamnuaychoke, Suporn Chuncharunee, Teerapong Siriboonpiputtana

Published in: Diagnostic Pathology | Issue 1/2021

Abstract

Objectives

TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients.

Methods

Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA).

Results

A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients.

Discussion

In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

Rucker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119(9):2114–21. https://doi.org/10.1182/blood-2011-08-375758.CrossRefPubMed

Hou HA, Chou WC, Kuo YY, Liu CY, Lin LI, Tseng MH, et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Blood Cancer J. 2015;5(7):e33. https://doi.org/10.1038/bcj.2015.59.CrossRef

Bowen D, Groves MJ, Burnett AK, Patel Y, Allen C, Green C, et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia. 2009;23(1):203–6. https://doi.org/10.1038/leu.2008.173.CrossRefPubMed

Prochazka KT, Pregartner G, Rücker FG, Heitzer E, Pabst G, Wölfler A, et al. Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. Haematologica. 2019;104(3):516–23. https://doi.org/10.3324/haematol.2018.205013.CrossRefPubMedPubMedCentral

Rampal R, Ahn J, Abdel-Wahab O, Nahas M, Wang K, Lipson D, et al. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014;111(50):5401–10. https://doi.org/10.1073/pnas.1407792111.CrossRef

Horiike S, Misawa S, Kaneko H, Sasai Y, Kobayashi M, Fujii H, et al. Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia withchromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype. Leukemia. 1999;13(8):1235–42. https://doi.org/10.1038/sj.leu.2401466.CrossRefPubMed

Kulasekararaj AG, Smith AE, Mian SA, Mohamedali AM, Krishnamurthy P, Lea NC, et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol. 2013;160(5):660–72. https://doi.org/10.1111/bjh.12203.CrossRefPubMed

Haase D, Stevenson KE, Neuberg D, Maciejewski JP, Nazha A, Sekeres MA, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33(7):1747–58. https://doi.org/10.1038/s41375-018-0351-2.CrossRefPubMedPubMedCentral

Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408(6810):307–10. https://doi.org/10.1038/35042675.CrossRefPubMed

10.

Hunter AM, Sallman DA. Current status and new treatment approaches in TP53 mutated AML. Best Pract Res Clin Haematol. 2019;32(2):134–44. https://doi.org/10.1016/j.beha.2019.05.004.CrossRefPubMed

11.

Barbosa K, Li S, Adams PD, Deshpande AJ. The role of TP53 in acute myeloid leukemia: challenges and opportunities. Genes Chromosomes Cancer. 2019;58(12):875–88. https://doi.org/10.1002/gcc.22796.CrossRefPubMed

12.

Sallman DA, Komrokji R, Vaupel C, Cluzeau T, Geyer SM, McGraw KL, et al. Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes. Leukemia. 2016;30(3):666–73. https://doi.org/10.1038/leu.2015.304.CrossRefPubMed

13.

Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Medina-Martinez JS, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26(10):1549–56. https://doi.org/10.1038/s41591-020-1008-z.CrossRefPubMedPubMedCentral

14.

Polprasert C, Takeda J, Niparuck P, Rattanathammethee T, Pirunsarn A, Suksusut A, et al. Novel DDX41 variants in Thai patients with myeloid neoplasms. Int J Hematol. 2020;111(2):241–6. https://doi.org/10.1007/s12185-019-02770-3.CrossRefPubMed

15.

Yu Y, Zhang T, Bao X, Wang Q, Zhang L, Hong Y, et al. Combining gene variants with clinical characteristics improves outcome prediction in Chinese patients with myelodysplastic syndromes. Leuk Lymphoma. 2020;61(4):919–26. https://doi.org/10.1080/10428194.2019.1702177.CrossRefPubMed

16.

Xu Y, Li Y, Xu Q, Chen Y, Lv N, Jing Y, et al. Implications of mutational spectrum in myelodysplastic syndromes based on targeted next-generation sequencing. Oncotarget. 2017;8(47):82475–90. https://doi.org/10.18632/oncotarget.19628.CrossRefPubMedPubMedCentral

17.

Yoshizato T, Nannya Y, Atsuta Y, Shiozawa Y, Iijima-Yamashita Y, Yoshida K, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129(17):2347–58. https://doi.org/10.1182/blood-2016-12-754796.CrossRefPubMedPubMedCentral

18.

Jiang Y, Eveillard JR, Couturier MA, Soubise B, Chen JM, Gao S, et al. Asian population is more prone to develop high-risk myelodysplastic syndrome, concordantly with their propensity to exhibit high-risk cytogenetic aberrations. Cancers (Basel). 2021;13(3):481. https://doi.org/10.3390/cancers13030481.CrossRef

19.

Abinaya P, Ling SH, Seah E, Ng C, Kosmo B, Yan B, et al. Clinical implications of TP53 mutations in a southeast Asian cohort of acute myeloid leukaemia patients. Clin Diagn Pathol. 2018;2(2):1–6. https://doi.org/10.15761/CDP.1000129.CrossRef

20.

Xiang X, Ou Y, Wu Y. Comparison the Distinct Clinical Outcome with TP53 Mutation Status in MDS and AML: an Retrospective Study. Blood. 2019;134(Supplement_1):5405.CrossRef

21.

Dutta S, Pregartner G, Rücker FG, Heitzer E, Zebisch A, Bullinger L, et al. Functional classification of TP53 Mutations in acute myeloid leukemia. Cancers (Basel). 2020;12(3):637.CrossRef

22.

Belickova M, Vesela J, Jonasova A, Pejsova B, Votavova H, Merkerova MD, et al. TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes. Oncotarget. 2016;7(24):36266–79. https://doi.org/10.18632/oncotarget.9200.CrossRefPubMedPubMedCentral

Title: TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome
Authors: Pimjai Niparuck
Pornnapa Police
Phichchapha Noikongdee
Kanchana Siriputtanapong
Nittaya Limsuwanachot
Budsaba Rerkamnuaychoke
Suporn Chuncharunee
Teerapong Siriboonpiputtana
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Myelodysplastic Syndrome
Acute Myeloid Leukemia
Published in: Diagnostic Pathology / Issue 1/2021
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/s13000-021-01162-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

Abstract

Objectives

Methods

Results

Discussion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Methods

Results

Discussion

Please log in to get access to this content

Other articles of this Issue 1/2021

Down-regulation of SOCS6: an unfavorable prognostic factor for gastrointestinal stromal tumor proven by survival analysis

Extranodal natural killer/T-cell lymphoma nasal type with extensive ocular tissue involvement: a case report

Inflammatory pseudotumor of Castleman disease and IgG4-related disease masquerading as kidney malignancy

High miR-324-5p expression predicts unfavorable prognosis of gastric cancer and facilitates tumor progression in tumor cells

Congenital hepatic fibrosis and its mimics: a clinicopathologic study of 19 cases at a single institution

Long non-coding RNA DUXAP8 elevates RCN2 expression and facilitates cell malignant behaviors and angiogenesis in cervical cancer via sponging miR-1297