Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients.

Autor: Halik A; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Tilgner M; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Silva P; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Estrada N; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Altwasser R; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Jahn E; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Heuser M; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.; Department of Internal Medicine IV, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany., Hou HA; Division of Hematology, Department of Internal Medicine, and Division of General Medicine, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung Shan South Road, Taipei City, Taiwan., Pratcorona M; Hospital de la Santa Creu i Sant Pau. Institut de Recerca Sant Pau. Department of Medicine, Universitat Autonoma of Barcelona, Barcelona, Spain., Hills RK; Nuffield Department of Population Health, University of Oxford, Oxford, UK., Metzeler KH; Department of Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany., Fenwarth L; Unité Mixte de Recherche (UMR) 9020-UMR1277, Canther-Cancer Heterogeneity, Plasticity and Resistance to Therapies, University of Lille, Centre National de la Recherche Scientifique (CNRS), INSERM, Centre Hospitalo-Universitaire (CHU) Lille, Institut de Recherche sur le Cancer de Lille (IRCL), Lille, France., Dolnik A; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Terre C; Laboratoire de Cytogénétique, Service de Biologie, CH de Versailles, Le Chesnay, France., Kopp K; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Blau O; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Szyska M; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Christen F; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Krönke J; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; German Cancer Consortium (Deutsches Konsortium Für Translationale Krebsforschung, DKTK), Partner Site, Berlin, Germany., Vasseur L; Hematology Department, Saint Louis Hospital, AP-HP, Paris, France., Löwenberg B; Department of Hematology, Erasmus MC Cancer Institute, and Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands., Esteve J; Hematology Department, IDIBAPS, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain., Valk PJM; Department of Hematology, Erasmus MC Cancer Institute, and Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands., Duchmann M; Institut de Recherche Saint-Louis (IRSL), Institut National de la Santé et de la Recherche Médicale (INSERM) U944, Centre National de la Recherche Scientifique (CNRS) UMR 7212 GenCellDis, Université Paris Cité, Paris, France., Chou WC; Division of Hematology, Department of Internal Medicine, and Division of General Medicine, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung Shan South Road, Taipei City, Taiwan., Linch DC; Department of Haematology, University College London Cancer Institute, London, UK., Döhner H; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Gale RE; Department of Haematology, University College London Cancer Institute, London, UK., Döhner K; Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany., Bullinger L; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; German Cancer Consortium (Deutsches Konsortium Für Translationale Krebsforschung, DKTK), Partner Site, Berlin, Germany., Yoshida K; Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan., Damm F; Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. frederik.damm@charite.de.; German Cancer Consortium (Deutsches Konsortium Für Translationale Krebsforschung, DKTK), Partner Site, Berlin, Germany. frederik.damm@charite.de.
Jazyk: angličtina
Zdroj: Journal of hematology & oncology [J Hematol Oncol] 2024 Aug 19; Vol. 17 (1), pp. 70. Date of Electronic Publication: 2024 Aug 19.
DOI: 10.1186/s13045-024-01590-1
Abstrakt: Background: Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood.
Methods: To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines.
Results: In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7-most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or -7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66-3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56-3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25-4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33-4.04]; P = 0.003). By contrast, IDH2-mutated patients (9%) displayed prolonged OS (HR, 0.51 [95% CI 0.30-0.88]; P = 0.0015) and durable responses (RFS: HR, 0.5 [95% CI 0.26-0.96]; P = 0.036).
Conclusion: This work unraveled formerly underestimated genetic lesions and provides a comprehensive overview of the spectrum of recurrent gene mutations and their clinical relevance in AML with abn(7). KMT2C mutations are among the most frequent gene mutations in this heterogeneous AML subgroup and warrant further functional investigation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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