Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients
Por:
Halik, A, Tilgner, M, Silva, P, Estrada, N, Altwasser, R, Jahn, E, Heuser, M, Hou, HA, Pratcorona, M, Hills, RK, Metzeler, KH, Fenwarth, L, Dolnik, A, Terre, C, Kopp, K, Blau, O, Szyska, M, Christen, F, Krönke, J, Vasseur, L, Löwenberg, B, Esteve, J, Valk, PJM, Duchmann, M, Chou, WC, Linch, DC, Döhner, H, Gale, RE, Döhner, K, Bullinger, L, Yoshida, K, Damm, F
Publicada:
19 ago 2024
Resumen:
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.
Filiaciones:
Halik, A:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Tilgner, M:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Silva, P:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Estrada, N:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Altwasser, R:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Jahn, E:
Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
Heuser, M:
Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpla, Hannover, Germany
Martin Luther Univ Halle Wittenberg, Univ Hosp Halle Saale, Dept Internal Med 4, Halle, Germany
Hou, HA:
Natl Taiwan Univ Hosp, Dept Internal Med, Div Hematol, 7 Chung Shan South Rd, Taipei City, Taiwan
Natl Taiwan Univ Hosp, Dept Internal Med, Div Gen Med, 7 Chung Shan South Rd, Taipei City, Taiwan
Pratcorona, M:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Inst Recerca St Pau, Dept Med, Barcelona, Spain
Hills, RK:
Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England
Metzeler, KH:
Univ Hosp Leipzig, Dept Hematol Cell Therapy Hemostaseol & Infect Dis, Leipzig, Germany
Fenwarth, L:
Univ Lille, Inst Rech Canc Lille IRCL, CNRS, Ctr Hosp Univ CHU Lille,Unite Mixte Rech UMR 9020,, Lille, France
Dolnik, A:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Terre, C:
CH Versailles, Serv Biol, Lab Cytogenet, Le Chesnay, France
Kopp, K:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Blau, O:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Szyska, M:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Christen, F:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
Krönke, J:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
German Canc Consortium, DKTK, Partner Site, Deutsch Konsortium Translationale Krebsforsch, Berlin, Germany
Vasseur, L:
St Louis Hosp, Hematol Dept, AP HP, Paris, France
Löwenberg, B:
Erasmus MC Canc Inst, Dept Hematol, Rotterdam, Netherlands
Erasmus MC, Rotterdam, Netherlands
Esteve, J:
Univ Barcelona, Hosp Clin Barcelona, Hematol Dept, IDIBAPS, Barcelona, Spain
Valk, PJM:
Erasmus MC Canc Inst, Dept Hematol, Rotterdam, Netherlands
Erasmus MC, Rotterdam, Netherlands
Duchmann, M:
Univ Paris Cite, Inst Rech St Louis IRSL, CNRS, UMR 7212,Inst Natl Sante & Rech Med,INSERM,U944,Ge, Paris, France
Chou, WC:
Natl Taiwan Univ Hosp, Dept Internal Med, Div Hematol, 7 Chung Shan South Rd, Taipei City, Taiwan
Natl Taiwan Univ Hosp, Dept Internal Med, Div Gen Med, 7 Chung Shan South Rd, Taipei City, Taiwan
Linch, DC:
Univ Coll London Canc Inst, Dept Haematol, London, England
Döhner, H:
Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
Gale, RE:
Univ Coll London Canc Inst, Dept Haematol, London, England
Döhner, K:
Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
Bullinger, L:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
German Canc Consortium, DKTK, Partner Site, Deutsch Konsortium Translationale Krebsforsch, Berlin, Germany
Yoshida, K:
Natl Canc Ctr, Div Canc Evolut, Tokyo, Japan
Damm, F:
Charite Univ Med Berlin, Dept Hematol Oncol & Canc Immunol, Berlin, Germany
Free Univ Berlin, Berlin, Germany
Humboldt Univ, Berlin, Germany
Berlin Inst Hlth, Berlin, Germany
German Canc Consortium, DKTK, Partner Site, Deutsch Konsortium Translationale Krebsforsch, Berlin, Germany
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