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

• DOI: 10.1186/s13045-024-01590-1
• Publication Date: 2024-08-19T07:02:17Z
• Authors: Adriane Halik; Marlon Tilgner; Patricia Silva; Natalia Estrada; Robert Altwasser; Ekaterina Jahn; Michael Heuser; Hsin-An Hou; Marta Pratcorona; Robert K. Hills; Klaus H. Metzeler; Laurene Fenwarth; Anna Dolnik; Christine Terre; Klara Kopp; Olga Blau; Martin Szyska; Friederike Christen; Jan Krönke; Loïc Vasseur; Bob Löwenberg; Jordi Esteve; Peter J. M. Valk; Matthieu Duchmann; Wen-Chien Chou; David C. Linch; Hartmut Döhner; Rosemary E. Gale; Konstanze Döhner; Lars Bullinger; Kenichi Yoshida; Frederik Damm
• Keywords: Male; Adult; 0301 basic medicine; Cancer Research; Adolescent; DNA Copy Number Variations; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Monosomy 7; Cohort Studies; Young Adult; 03 medical and health sciences; SDG 3 - Good Health and Well-being; AML; del(7q); Exome Sequencing; Humans; Diseases of the blood and blood-forming organs; TP53; RC254-282; Aged; Chromosome Aberrations; Aged, 80 and over; Complex karyotype; Research; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; KMT2C; Genomics; Middle Aged; Prognosis; Leukemia, Myeloid, Acute; Mutation; Female; RC633-647.5; Tumor Suppressor Protein p53; Chromosomes, Human, Pair 7

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.