Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma with a large number of recurrent cytogenetic/molecular aberrations. Approximately 5-10% of patients do not respond to frontline immunochemotherapy. Despite many useful prognostic indexes, a reliable marker of chemoresistance is not available. We evaluated the prognostic impact of seven recurrent gene aberrations including tumor suppressor protein P53 (TP53) and cyclin dependent kinase inhibitor 2A (CDKN2A) in the cohort of 126 newly diagnosed consecutive MCL patients with bone marrow involvement ≥5% using fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS). In contrast to TP53, no pathologic mutations of CDKN2A were detected by NGS. CDKN2A deletions were found exclusively in the context of other gene aberrations suggesting it represents a later event (after translocation t(11;14) and aberrations of TP53, or ataxia telangiectasia mutated (ATM)). Concurrent deletion of CDKN2A and aberration of TP53 (deletion and/or mutation) represented the most significant predictor of short EFS (median 3 months) and OS (median 10 months). Concurrent aberration of TP53 and CDKN2A is a new, simple, and relevant index of chemoresistance in MCL. Patients with concurrent aberration of TP53 and CDKN2A should be offered innovative anti-lymphoma therapy and upfront consolidation with allogeneic stem cell transplantation.

1st Department of Internal Medicine Hematology General University Hospital and 1st Faculty of Medicine Charles University Prague 12808 Prague Czech Republic

Center of Oncocytogenomics Institute of Clinical Biochemistry and Laboratory Diagnostics General University Hospital and 1st Faculty of Medicine Charles University Prague 12853 Prague Czech Republic

CLIP Department of Pediatric Hematology Oncology 2nd Faculty of Medicine and University Hospital in Motol 15006 Prague Czech Republic

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc 77515 Olomouc Czech Repulbic

Institute of Pathological Physiology 1st Faculty of Medicine Charles University Prague 12853 Prague Czech Republic

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