title: Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations.
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.
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Wu
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Noel Fcc
authors.initials: NF
authors.lastname: de Miranda
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.|Beijing Genomics Institute, Shenzhen, China.
authors.forename: Longyun
authors.initials: L
authors.lastname: Chen
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Agata M
authors.initials: AM
authors.lastname: Wasik
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.affiliation: Department of Hematology, Jagiellonian University Collegium Medicum, Kraków, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jurczak
authors.affiliation: Department of Pathology, Jagiellonian University Collegium Medicum, Kraków, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Galazka
authors.affiliation: Department of Hematology, Jagiellonian University Collegium Medicum, Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Dlugosz-Danecka
authors.affiliation: Faculty of Health Sciences, Jagiellonian University Collegium Medicum, Michalowskiego, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Machaczka
authors.affiliation: Department of Lymphoma, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China.
authors.forename: Huilai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Roujun
authors.initials: R
authors.lastname: Peng
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.affiliation: Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pan-Hammarström
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018740:Genetic Heterogeneity; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012008:Recurrence; D015398:Signal Transduction; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection
chemical_list: D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D013792:Thalidomide; C426242:CARD11 protein, human; D006162:Guanylate Cyclase; D000077269:Lenalidomide; D000225:Adenine
keywords: CARD11; NF-κB inhibitor; mantle cell lymphoma; relapse; whole-exome sequencing