Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients.
Journal
Journal of Hematology and Oncology
ISSN
1756-8722
Date Issued
2024-08-19
Author(s)
Halik, Adriane
Tilgner, Marlon
Silva, Patricia
Estrada, Natalia
Altwasser, Robert
Jahn, Ekaterina
Heuser, Michael
Pratcorona, Marta
Hills, Robert K
Metzeler, Klaus H
Fenwarth, Laurene
Dolnik, Anna
Terre, Christine
Kopp, Klara
Blau, Olga
Szyska, Martin
Christen, Friederike
Krönke, Jan
Vasseur, Loïc
Löwenberg, Bob
Esteve, Jordi
Valk, Peter J M
Duchmann, Matthieu
Linch, David C
Döhner, Hartmut
Gale, Rosemary E
Döhner, Konstanze
Bullinger, Lars
Yoshida, Kenichi
Damm, Frederik
DOI
10.1186/s13045-024-01590-1
Abstract
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.
Subjects
IDH2
KMT2C
PTPN11
TP53
AML
Complex karyotype
Monosomy 7
del(7q)
SDGs
Publisher
BioMed Central Ltd
Description
Article number 70
Type
journal article