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Haematologica 2019 Volume 104(3):516-523
Acute Myeloid Leukemia
Clinical implications of subclonal TP53 mutations in acute myeloid leukemia
Katharina T. Prochazka,1* Gudrun Pregartner,2* Frank G. Rücker,3 Ellen Heitzer,4 Gabriel Pabst,1 Albert Wölfler,1 Armin Zebisch,1 Andrea Berghold,2 Konstanze Döhner3** and Heinz Sill1**
1Division of Hematology, Medical University of Graz, Austria; 2Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria; 3Department of Internal Medicine III, University Hospital of Ulm, Germany and 4Institute of Human Genetics, Medical University of Graz, Austria
*KTP and GP contributed equally to this work. **KD and HS contributed equally to this work.
ABSTRACT
The role of subclonal TP53 mutations, defined by a variant allele frequency of <20%, has not been addressed in acute myeloid leukemia yet. We, therefore, analyzed their prognostic value in a cohort of 1,537 patients with newly diagnosed disease, prospectively treated within three trials of the “German-Austrian Acute Myeloid Leukemia Study Group”. Mutational analysis was performed by targeted deep sequencing and patients with TP53 mutations were categorized by their variant allele frequency into groups with frequencies >40%, 20%- 40% and <20%. A total of 108 TP53 mutations were found in 98 patients (6.4%). Among these, 61 patients had variant allele frequencies >40%, 19 had variant allele frequencies between 20%-40% and 18 had frequencies <20%. Compared to specimens with clonal TP53 mutations, those with subclonal ones showed significantly fewer complex kary- otypes and chromosomal losses. In either TP53-mutated group, patients experienced significantly fewer complete responses (P<0.001) and had worse overall and event-free survival rates (P<0.0001). In Cox regression analyses adjusting for age, white blood cell count, cytogenetic risk and type of acute myeloid leukemia, the adverse prognostic effect of TP53 mutations remained significant for all TP53-mutated subgroups. These data suggest that subclonal TP53 mutations are a novel prognostic parameter in acute myeloid leukemia and emphasize the usefulness of next-generation sequencing technologies for risk stratification in this dis- order. The study was registered at ClinicalTrials.gov with number NCT00146120.
Introduction
Acute myeloid leukemia (AML) is an aggressive malignancy with an annual, age- adjusted incidence of 3.5 cases per 100,000 adults, rising to 15-20 cases per 100,000 above the age of 60 years.1 It, therefore, contributes substantially to morbidity and mortality of the elderly. The pathogenesis of AML represents a multistep process involving mutagenesis, epigenetic dysregulation and formation of copy number aberrations. During the process of leukemogenesis, initiating mutations affect hematopoietic stem and progenitor cells, giving rise to preleukemic/leukemic stem cells and, ultimately, frank leukemia. Virtually every AML genome is characterized by a number of subclones of variable size. These subclones may have different pathobiological properties as well as responses to antileukemic treatments.2-4
Aberrations of the TP53 tumor suppressor gene have been described in a variable number of cases of AML. They are present in less than 10% of cases of de novo AML, whereas their rates in therapy-related AML and erythroid leukemias exceed 20% and 90%, respectively.5-7 These aberrations include gene mutations, most of which are located within the DNA binding domain of the gene, and/or deletions of differ- ent sizes affecting the TP53 locus on chromosome 17p13. Although the majority of
Correspondence:
HEINZ SILL
heinz.sill@medunigraz.at
Received: August 21, 2018. Accepted: October 9, 2018. Pre-published: October 11, 2018.
doi:10.3324/haematol.2018.205013
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/516
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