Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations.

// Chenglin Wu 1 , Noel FCC de Miranda 1, * , Longyun Chen 1, 2, * , Agata M. Wasik 3, * , Larry Mansouri 4 , Wojciech Jurczak 5 , Krystyna Galazka 6 , Monika Dlugosz-Danecka 5 , Maciej Machaczka 7 , Huilai Zhang 8 , Roujun Peng 9 , Ryan D. Morin 10 , Richard Rosenquist 4 , Birgitta Sander 3 , Qiang Pan-Hammarstrom 1 1 Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden 2 Beijing Genomics Institute, Shenzhen, China 3 Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden 4 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden 5 Department of Hematology, Jagiellonian University Collegium Medicum, Krakow, Poland 6 Department of Pathology, Jagiellonian University Collegium Medicum, Krakow, Poland 7 Faculty of Health Sciences, Jagiellonian University Collegium Medicum, Michalowskiego, Poland 8 Department of Lymphoma, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China 9 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China 10 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada * These authors contributed equally to this work Correspondence to: Qiang Pan-Hammarstrom, email: Qiang.Pan-Hammarstrom@ki.se Keywords: whole-exome sequencing, mantle cell lymphoma, relapse, CARD11, NF-κB inhibitor Received: September 19, 2015      Accepted: May 01, 2016      Published: May 20, 2016 ABSTRACT The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known ( ATM, MEF2B and MLL2 ) and novel mutation targets ( S1PR1 and CARD11 ). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.