Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials

Leukemia, vol. 38, pp. 2675–2684

Abstract

Abstract Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay. The IGH::CCND1 fusion was identified in 94% of patients, clonal IGH-V-(D)-J rearrangements in all, and 79% had ≥1 somatic gene mutation. The top mutated genes were ATM , TP53 , KMT2D , SAMHD1 , BIRC3 and NFKBIE . Copy number variations (CNVs) were detected in 83% of patients with RB1 , ATM , CDKN2A/B and TP53 being the most frequently deleted and KLF2 , CXCR4 , CCND1 , MAP2K1 and MYC the top amplified genes. CNVs and mutations were more frequently observed in older patients with adverse impact on prognosis. TP53 mut , NOTCH1 mut , FAT1 mut TRAF2 del , CDKN2A/B del and MAP2K1 amp were linked to inferior failure-free (FFS) and overall survival (OS), while TRAF2 mut , EGR2 del and BCL2 amp related to inferior OS only. Genetic complexity (≥3 CNVs) observed in 51% of analysed patients was significantly associated with impaired FFS and OS. We demonstrate that targeted sequencing from peripheral blood and bone marrow reliably detects diagnostically and prognostically important genetic factors in MCL patients, facilitating genetic characterization in clinical routine.

Authors 12

1. Mouhamad Khouja

   University Hospital Schleswig-Holstein

   Affiliation as printed

   Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany

2. Linmiao Jiang

   Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, Germany

3. Karol Pál

   Masaryk University · Central European Institute of Technology – Masaryk University · University Hospital Schleswig-Holstein

   Affiliation as printed

   Center of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic

   Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany

4. Martin Schwarz

   University Hospital Schleswig-Holstein

   Affiliation as printed

   Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany

5. Stefan Alig

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Department of Medicine III, University Hospital, Ludwig-Maximilian-University, Munich, Germany

6. Nikos Darzentas

   University Hospital Schleswig-Holstein

   Affiliation as printed

   Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany

7. Hanneke C. Kluin‐Nelemans

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

8. Olivier Hermine

   Hôpital Necker-Enfants Malades · Centre National de la Recherche Scientifique · Inserm · Sorbonne Paris Cité · Assistance Publique – Hôpitaux de Paris · Institut des Maladies Génétiques Imagine · Université Paris Descartes

   Affiliation as printed

   Department of Hematology, Hôpital Necker, Assistance Publique Hôpitaux de Paris, University Paris Descartes, Paris, France

   INSERM U1163 and CNRS 8254, Imagine Institute, Université Sorbonne Paris Cité, Paris, France

9. Martin H. Dreyling

   Ludwig-Maximilians-Universität München

   Affiliation as printed

   Department of Medicine III, University Hospital, Ludwig-Maximilian-University, Munich, Germany

10. David González de Castro

    Queen's University Belfast

    Affiliation as printed

    The Patrick G Johnston Centre for Cancer Research, Queens University Belfast, Belfast, UK

11. Eva Hoster

    Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Institute for Medical Information Processing, Biometry and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, Germany

12. Christiane Pott corresponding

    University Hospital Schleswig-Holstein

    Affiliation as printed

    Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany. c.pott@med2.uni-kiel.de