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. TP53mut, NOTCH1mut, FAT1mut TRAF2del, CDKN2A/Bdel and MAP2K1amp were linked to inferior failure-free (FFS) and overall survival (OS), while TRAF2mut, EGR2del and BCL2amp 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.

2nd Medical Department University Hospital Schleswig Holstein Kiel Germany

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

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

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

Department of Medicine 3 University Hospital Ludwig Maximilian University Munich Germany

Department of Pathology Hematopathology Section and Lymph Node Registry University Hospital Schleswig Holstein Kiel Germany

Department of Pneumology and Intensive Care Medicine University Hospital RWTH Aachen Aachen Germany

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

Institute for Medical Information Processing Biometry and Epidemiology Faculty of Medicine LMU Munich Munich Germany

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

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