Concurrent BCL2 and MYC Protein Expression by Immunohistochemistry Determines Clinical Outcome In DLBCL Patients Treated with R-CHOP
Notice bibliographique
Résumé
Abstract Abstract 2005 Background: Concurrent translocations in MYC and BCL2 determined by fluorescence in-situ hybridization (FISH), have been associated with a poor outcome in diffuse large B cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, unlike immunohistochemistry (IHC), FISH is expensive and is not routinely available in all clinical laboratories. The aim of this study was to determine if MYC protein expression or expression of the proliferation marker Ki-67 by IHC could be used to identify samples that harbour MYC translocations. Methods: DLBCL samples, diagnosed by an expert panel of hematopathologists according to the WHO criteria of 2008 and derived from 167 patients treated with R-CHOP, have been subjected to gene expression profiling (GEP) and FISH using commercial break-apart probes for BCL2 and MYC. MYC mRNA expression was determined using log2 normalized expression values of probe set 202431_s_at. The presence of MYC, BCL2 and Ki-67 protein expression was determined by IHC using commercially available antibodies (clone Y69 (Epitomics), clone 124 (Dako) and clone Ki-67 (Dako) respectively). MYC protein is not normally expressed in germinal centers (tonsils, negative control), thus the % of tumour cells staining for MYC was noted in each case. Thresholds for BCL2 protein (50%) and MYC mRNA (>9.4) were determined using the statistical software X-tile which determines the optimal threshold based on its association with clinical outcome. For MYC protein expression, no threshold was significant by X-tile thus a 40% threshold was used based on the bimodal distribution of the data, with a through occurring at 40%. Protein expression for MYC and Ki-67 was correlated to the presence of MYC translocations, MYC mRNA expression and outcome including overall survival (OS) and progression free survival (PFS). Results: Over-expression of MYC was present in 56/167 (34%) of DLBCL samples (18/167 translocations, 19/167 high mRNA and 47/167 high protein expression) and was not specific to the germinal center B cell (GCB) or activated B cell (ABC) molecular subtype. MYC protein expression (in ≥40% of cells) captured 13/18 MYC translocations and in 4/5 remaining cases, MYC staining was present in 20–39% of cells. MYC protein expression, alone, was not associated with OS but the presence of a MYC translocation was associated with an inferior OS in the ABC subtype only. BCL2 protein expression was also associated with an inferior OS in this cohort (p=0.002). Concurrent expression of MYC and BCL2 protein by IHC was associated with a markedly inferior OS compared to MYC protein- or MYC protein+/BCL2 protein- (median OS of 2 years, 7 years and > 7 years respectively, p<0.001). In a Cox-multivariate model, the co-expression of MYC and BCL2 proteins by IHC maintained prognostic significance independent of the IPI (OS p=0.007, PFS p=0.008). In contrast, Ki-67 staining (>90%) identified only 5/18 cases with MYC translocations and was not associated with outcome alone or in combination with BCL2. Conclusions: MYC deregulation in DLBCL is more common than previously reported (34%) and can occur in the absence of a MYC translocation. MYC and BCL2 protein expression could be easily determined by routine IHC in most clinical laboratories and should be prospectively tested as potential predictive biomarkers in DLBCL patients treated with R-CHOP. Disclosures: Grogan: Ventana Roche: Employment, Equity Ownership.
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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 | 0,000 |
| 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) | 0,001 | 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 ».