BCL2 Is Highly Mutated In Diffuse Large B-Cell Lymphoma
Notice bibliographique
Résumé
Abstract Abstract 4187 Background. Diffuse large B-cell lymphomas (DLBCL), which comprise the most common subtype of non-Hodgkin lymphomas, can be further classified at the molecular level into activated B-cell (ABC) type and germinal centre B-cell (GCB) type. The t(14;18) translocation, which juxtaposes BCL2 to the immunoglobulin heavy gene, is frequent in the GCB subtype, while BCL2 can be up-regulated by gene amplifications and activation of the NF-kB pathway in the ABC subtype. We have recently recently re-sequenced DLBCL transcriptomes and have reported that EZH2 is recurrently mutated in the germinal center lymphomas (Morin et al., Nature Genetics 2010). This project also revealed that the gene containing the most variants was BCL2. The aim of this project was to determine the incidence and clinical significance of BCL2 mutations in a larger cohort of de novo DLBCL samples and matched germline in a subset of cases. In addition, the specificity of BCL2 to DLBCL was determined by sequencing the BCL2 gene in other lymphoma subtypes. Methods. 31 cases of DLBCL were subjected to whole transcriptome shotgun sequencing as part of the EZH2 study. The presence of BCL2 variants was determined using the Bayesian variant caller “SNVmix”. The BCL2 gene (exons 1–3) was re-sequenced using the Sanger method in a total of 514 samples, of which 349 cases were primary DLBCL, 30 were small lymphocytic lymphoma (SLL), 26 were follicular lymphoma (FL), 25 were mantle cell lymphoma (MCL), 25 were peripheral T cell lymphoma, 8 were purified centroblasts and 51 were germline DNA from patients who had DLBCL or FL in this study. The presence of the translocation t(14;18) was determined by fluorescence in situ hybridization in 145 DLBCL samples and by karyotype in 26 FL samples. The presence of BCL2 protein expression was determined using clone 124 (Dako) in 284 cases. The association between the presence of mutations and other variables was determined using the Fisher's exact test and the association to overall survival (OS) was determined using the log Rank test. Results. In whole transcriptome shotgun sequencing of 31 DLBCL samples, we found BCL2 to contain expressed point mutations in 11/31 cases, including a total of 19 non-synonymous mutations and 30 synonymous mutations. Sanger sequencing revealed BCL2 mutations in 117/349 DLBCL, 22/26 FL, 3/25 MCL, 1/30 SLL and 2/25 PTCL and no mutations were identified in the germline samples or purified centroblasts. The presence of BCL2 mutations was associated with the GCB phenotype (p = 7.6×10-7) and was enriched in t(14;18)-positive cases. The ratio of transitions to transversions was 1.47, suggestive that these mutations were inserted as a consequence of somatic hypermutation (p = 6.28 × 10-21). Non-synonymous mutations occurred in 41 DLBCL cases and were predominantly located in the flexible loop domain and between the BH1 and BH3 domains while sparing all the BH domains, which are responsible for anti-apoptotic function. Despite this, BCL2 protein was present in 238/284 cases using the Dako antibody. Non-synonymous mutations in BCL2 were not associated with an inferior OS or PFS, even within the GCB subtype. Conclusions. BCL2 mutations in DLBCL and FL are much more prevalent than previously anticipated and appear to be a consequence of on-going somatic hypermutation in the germinal center. The functional and clinical significance of these mutations should be studied further, given that BH3 mimetics may eventually be considered as therapeutic options in these patients. Disclosures: No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».