Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent <i>CARD11</i> mutations
Bibliographic record
Abstract
// 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-Hammarström 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, Kraków, Poland 6 Department of Pathology, Jagiellonian University Collegium Medicum, Kraków, 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-Hammarström, 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".