TP53 Mutation Status in Myelodysplastic Neoplasm and Acute Myeloid Leukemia: Impact of Reclassification Based on the 5th WHO and International Consensus Classification Criteria: A Korean Multicenter Study
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Ann Lab Med 2023; 43(5): 503-507
Published online April 21, 2023 https://doi.org/10.3343/alm.2023.43.5.503
Copyright © Korean Society for Laboratory Medicine.
Cheonghwa Lee , M.D.1, Ha Nui Kim , M.D., Ph.D.1, Jung Ah Kwon , M.D., Ph.D.1, Soo-Young Yoon , M.D., Ph.D.1, Min Ji Jeon , M.D., Ph.D.2, Eun Sang Yu , M.D.2, Dae Sik Kim , M.D., Ph.D.2, Chul Won Choi , M.D., Ph.D.2, and Jung Yoon, M.D., Ph.D.1
1Department of Laboratory Medicine, College of Medicine, Korea University Seoul, Korea; 2Division of Hematology-Oncology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea
Correspondence to: Jung Yoon, M.D., Ph.D.
Department of Laboratory Medicine, Guro Hospital, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea
Tel: +82-2-2626-3242
Fax: +82-2-2626-1465
E-mail: unoaotro@korea.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The fifth edition of the WHO classification (2022 WHO) and the International Consensus Classification (2022 ICC) of myeloid neoplasms have been recently published. We reviewed the changes in the diagnosis distribution in patients with MDS with excess blasts (MDS-EB) or AML using both classifications. Forty-seven patients previously diagnosed as having AML or MDS-EB with available mutation analysis data, including targeted next-generation and RNA-sequencing data, were included. We reclassified 15 (31.9%) and 27 (57.4%) patients based on the 2022 WHO and 2022 ICC, respectively. One patient was reclassified as having a translocation categorized as a rare recurring translocation in both classifications. Reclassification was mostly due to the addition of mutation-based diagnostic criteria (i.e., AML, myelodysplasia-related) or a new entity associated with TP53 mutation. In both classifications, MDS diagnosis required the confirmation of multi-hit TP53 alterations. Among 14 patients with TP53 mutations, 11 harbored multi-hit TP53 alterations, including four with TP53 mutations and loss of heterozygosity. Adverse prognosis was associated with multi-hit TP53 alterations (P=0.009) in patients with MDS-EB, emphasizing the importance of detecting the mutations at diagnosis. The implementation of these classifications may lead to the identification of different subtypes from previously heterogeneous diagnostic categories based on genetic characteristics.
Keywords: Myelodysplastic syndrome, Acute myeloid leukemia, Prognosis, World Health Organization, Mutation, TP53
Genome studies of myeloid hematological malignancies, including AML and MDS, have advanced our understanding of these diseases and revealed molecularly distinct groups [1–4]. Recently, the fifth edition of the WHO classification (2022 WHO) and the International Consensus Classification (2022 ICC) of myeloid neoplasms were published [5, 6]. In both classifications, the major changes regarding AML and MDS include: (1) changes in the blast thresholds defining AML, including the expansion of the genetic abnormality categories that may be diagnosed as AML with a blast cut-off requirement of 10%; (2) the introduction of an AML classification subtype termed “rare recurring translocation”; and (3) the extension of mutation-based definitions [5–7]. We reclassified patients diagnosed as having AML and MDS with excess blasts (MDS-EB) according to the 2016 WHO classification (2016 WHO), using the 2022 WHO and 2022 ICC. As the blast percentage defining MDS-EB and AML has been lowered and various genetic alterations have been introduced in both classifications, we reviewed the changes in the diagnosis distribution of patients with MDS-EB and AML using both the 2022 WHO and 2022 ICC. In addition, we focused on a newly introduced classification category, including
Forty-seven adult patients diagnosed as having AML or MDS-EB between November 2019 and September 2021 with available mutation analysis data, including targeted next-generation and RNA-sequencing data, were included in our study. Patients with AML with 2016 WHO-designated recurring balanced translocations were excluded (Fig. 1). This study was approved by the Institutional Review Board of Korea University, Guro Hospital, Seoul, Korea (2021GR0247, 2021GR0572). Overall patient characteristics are provided in Supplemental Data Table S1.
We retrospectively reviewed the clinical responses of all patients and conducted a survival analysis. Cytogenetic abnormalities were analyzed according to the 2020 International System for Human Cytogenomic Nomenclature guidelines [8]. Sequence data were mapped to the reference genome GrCH37 (hg19). Mutation analysis was performed using the Oncomine Myeloid Research Assay (Thermo Fisher Scientific, Waltham, MA, USA). Libraries were prepared using the Ion Chef System (Thermo Fisher Scientific) and sequenced using an Ion S5 XL sequencer (Thermo Fisher Scientific). Alignment and base calling were performed using Torrent Suite (v5.10), and variant calling was performed using Ion Reporter (v5.10). The variant allele fraction (VAF) cut-off for missense and nonsense variants was 5% and 10%, respectively, for insertions/deletions. RNA-sequencing libraries were prepared using the TruSeq Stranded Total RNA LT sample preparation kit (Illumina, San Diego, CA, USA) and sequenced using the NovaSeq platform (Illumina). Sequencing reads were aligned using the STAR aligner (v2.6.0), and fusion transcripts were detected using Arriba (v2.2.0) [9, 10]. For samples with
Although the genetic abnormality categories that may be diagnosed as AML with a blast cut-off requirement of 10% have been expanded, patients with MDS-EB that were reclassified as AML were not observed. Among the 37 patients with AML, AML with recurrent genetic abnormalities accounted for 45.9% (17/37) according to the 2016 WHO, whereas 32.4% (12/37) of patients with AML were classified as AML with defining genetic abnormalities according to the 2022 WHO and as AML with recurrent genetic abnormalities according to the 2022 ICC (Fig. 2). Because of the exclusion of the provisional entity of AML with mutated
AML with myelodysplasia-related changes (AML-MRC) accounted for 24.3% (9/37) of the patients with AML according to the 2016 WHO; an increase in patients classified as AML, MR according to the 2022 WHO (45.9%, N=17/37) and AML with MR gene mutation or AML with MR cytogenetic abnormalities according to the 2022 ICC (32.4%, N=12/37) was noted when compared to the classification according to the 2016 WHO (Fig. 2). With the introduction of the mutation-based definition of AML, MR, in addition to patients with AML with mutated
Among the 47 patients, 14 patients (six with MDS-EB, seven with AML, and one with therapy-related myeloid neoplasms) harbored
Using the 2022 WHO and 2022 ICC, we reclassified 15 (31.9%) and 27 (57.4%) out of 47 patients, respectively. This result was most likely a consequence of the addition of mutation-based definitions in the diagnostic criteria of AML, MR and the introduction of new entities, such as myeloid neoplasms with mutated
In summary, the 2022 WHO and 2022 ICC identified different subtypes from previously heterogeneous diagnostic categories based on genetic characteristics. Changes in the blast thresholds for defining AML in some genetic abnormality categories were not associated with the major reclassified cases in the clinical setting.
None.
Yoon SY and Yoon J contributed to the study conception and design; Kim HN, Kwon JA, Jeon MJ, Yu ES, Kim DS, and Choi CW were involved in clinical evaluation; Lee C, Yoon SY, and Yoon J interpreted the results; Lee C and Yoon J statistically analyzed the data; Lee C and Yoon J drafted the manuscript; and Yoon J supervised the study. All authors read and approved the final manuscript.
None declared.
This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (2022R1G1A1007629) and a grant funded by Korea University (K2023141).