Prognostic implications of BCL6 rearrangement in uniformly treated patients with diffuse large B cell lymphoma—a Nordic Lymphoma Group study

Department of Oncology, Lund University Hospital, SE-221 85 Lund, Sweden.
International Journal of Oncology (Impact Factor: 3.03). 02/2002; 20(1):161-5. DOI: 10.3892/ijo.20.1.161
Source: PubMed


The purpose of this study was to investigate the prognostic implications of BCL6 rearrangement in a uniformly treated population of patients with diffuse large B-cell lymphoma (DLBCL) and to characterise the relationship between BCL6 rearrangement and prognostic factors. A total of 269 patients with DLBCL entered a randomised trial comparing the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimen. In 44 cases, frozen tissue was available for assessment of BCL6 status by Southern blot analysis. BCL6 was rearranged in six of 43 evaluable cases (14%), and was associated with elevated lactate dehydrogenase (LDH), and a higher patient age. No association between BCL6 status and expression of BCL2, Ki-67 or TP53 was found. Patients presenting with BCL6 rearrangement displayed a weak trend towards better overall and failure-free survival (67 and 67% at 5 years), compared to patients with germline BCL6 (63 and 52%), but the difference was not statistically significant. In accordance with previously published series, the presence of BCL6 rearrangement does not define a prognostically distinct subgroup of DLBCL. Assessment of BCL6 status may, however, be of clinical interest when related to other prognostic variables.

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    • "Although previous studies have reported that translocations may indicate a favorable prognosis [20] [21] [53], an unfavorable prognosis [17] [54], or no effect [14] [21], in our study, Bcl-6 translocation combined with a high expression of Bcl-6 and p53 genes appears to be a poor prognostic indicator and a potential new gene marker for gliomas. "
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    ABSTRACT: Bcl-6 translocation is a genetic alteration that is commonly detected in Primary Central Nervous System Lymphoma. The role of this protein in cerebral tumors is unclear. In this study we investigated Bcl-6 translocation and its transcriptional and translational levels in formalin-fixed, paraffin-embedded cerebral tissue sections from Glioblastoma (GBM), low-grade glioma (Astrocytoma grade II and III), and meningioma patients, and correlated them with apoptotic processes and p53 and caspase-3 expression. The results showed a frequency of 36.6% of Bcl-6 translocation in GBM patients and a decreased expression in low-grade glioma patients, correlated with the severity of the disease. Bcl-6 translocation induced an overexpression of both Bcl-6 protein and messenger in GBM, inhibiting apoptotic processes and caspases 3 expression. On the contrary, in low-grade gliomas and meningiomas Bcl-6 expression was reduced, resulting in an increase of apoptotic processes. Finally, p53 expression levels in brain tumors were comparable to Bcl-6 levels. Overall, these data demonstrate, for the first time, that the Bcl-6 gene translocates in GBM patients and that its translocation and expression are correlated with apoptosis inhibition, indicating a key role for this gene in the control of cellular proliferation. This study offers further insights into Glioblastoma biology, and supports Bcl-6 as a new diagnostic marker to evaluate the disease severity.
    Cancer Letters 10/2014; 353(1):41. DOI:10.1016/j.canlet.2014.06.017 · 5.62 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas. As DLBCL is characterized by heterogeneous clinical and biological features, its prognosis varies. To date, the International Prognostic Index has been the strongest predictor of outcome for DLBCL patients. However, no biological characters of the disease are taken into account. Gene expression profiling studies have identified two major cell-of-origin phenotypes in DLBCL with different prognoses, the favourable germinal centre B-cell-like (GCB) and the unfavourable activated B-cell-like (ABC) phenotypes. However, results of the prognostic impact of the immunohistochemically defined GCB and non-GCB distinction are controversial. Furthermore, since the addition of the CD20 antibody rituximab to chemotherapy has been established as the standard treatment of DLBCL, all molecular markers need to be evaluated in the post-rituximab era. In this study, we aimed to evaluate the predictive value of immunohistochemically defined cell-of-origin classification in DLBCL patients. The GCB and non-GCB phenotypes were defined according to the Hans algorithm (CD10, BCL6 and MUM1/IRF4) among 90 immunochemotherapy- and 104 chemotherapy-treated DLBCL patients. In the chemotherapy group, we observed a significant difference in survival between GCB and non-GCB patients, with a good and a poor prognosis, respectively. However, in the rituximab group, no prognostic value of the GCB phenotype was observed. Likewise, among 29 high-risk de novo DLBCL patients receiving high-dose chemotherapy and autologous stem cell transplantation, the survival of non-GCB patients was improved, but no difference in outcome was seen between GCB and non-GCB subgroups. Since the results suggested that the Hans algorithm was not applicable in immunochemotherapy-treated DLBCL patients, we aimed to further focus on algorithms based on ABC markers. We examined the modified activated B-cell-like algorithm based (MUM1/IRF4 and FOXP1), as well as a previously reported Muris algorithm (BCL2, CD10 and MUM1/IRF4) among 88 DLBCL patients uniformly treated with immunochemotherapy. Both algorithms distinguished the unfavourable ABC-like subgroup with a significantly inferior failure-free survival relative to the GCB-like DLBCL patients. Similarly, the results of the individual predictive molecular markers transcription factor FOXP1 and anti-apoptotic protein BCL2 have been inconsistent and should be assessed in immunochemotherapy-treated DLBCL patients. The markers were evaluated in a cohort of 117 patients treated with rituximab and chemotherapy. FOXP1 expression could not distinguish between patients, with favourable and those with poor outcomes. In contrast, BCL2-negative DLBCL patients had significantly superior survival relative to BCL2-positive patients. Our results indicate that the immunohistochemically defined cell-of-origin classification in DLBCL has a prognostic impact in the immunochemotherapy era, when the identifying algorithms are based on ABC-associated markers. We also propose that BCL2 negativity is predictive of a favourable outcome. Further investigational efforts are, however, warranted to identify the molecular features of DLBCL that could enable individualized cancer therapy in routine patient care. Diffuusi suurisoluinen B-solulymfooma (DLBCL) on yleisin imukudossyövistä, eli non-Hodgkin lymfoomista. Taudin ennuste on vaihteleva taudin heterogeenisistä piirteistä johtuen. Immunokemoterapia, eli CD20 vasta-aineen, rituksimabin, ja monisolunsalpaajien yhdistelmä on DLBCL potilaiden ensilinjan hoito. Tärkein DLBCL potilaan ennustetta määrittävä tekijä on kliinisiin parametreihin perustuva luokitus. Kuitenkin myös taudin biologisilla piirteillä on vaikutus taudin kulkuun. DLBCL on jaoteltu hyväennusteisiin itukeskusperäisiin ja huonoennusteisiin ei-itukeskusperäisiin alatyyppeihin. Näiden alatyyppien ennusteellinen merkitys on kuitenkin ollut epäselvä immunokemoterapian aikakaudella. Tämän väitöskirjan tavoitteena oli selventää immunohistokemiallisesti määriteltyjen biologisten ennustetekijöiden merkitys immunokemoterapiaa saaneilla DLBCL potilailla. Tutkimuksessa todettiin että aikaisemmin esitellyn algoritmin mukaan (CD10, BCL6 ja MUM1/IRF4) itukeskus ja ei-itukeskus alatyyppistä lymfoomaa sairastavilla potilailla ei ollut eroa taudinkulussa. Luokittelulla ei myöskään ollut ennusteellista merkitystä potilailla, joiden hoitona oli ollut korkea-annossolunsalpaajahoito ja autologinen kantasolusiirto. Sen sijaan, mikäli ei-itukeskus alatyyppi määriteltiin väitöskirjassa kuvatun uuden algoritmin mukaan (MUM1/IRF4 ja FOXP1) voitiin todeta, että tämän alatyypin omaavilla potilailla oli immunokemoterapian jälkeen huonompi ennuste kuin muilla potilailla. Väitöskirjassa tutkittiin lisäksi immunohistokemiallisesti BCL2 ja FOXP1 proteiinien ilmentyminen lymfoomakudoksessa ja niiden ennusteellista merkitystä immunokemoterapiaa saaneilla DLBCL potilailla. Tutkimuksessa todettiin, että potilailla oli huono ennuste, jos BCL2 proteiinia todettiin lymfoomakudoksessa. FOXP1 proteiinilla ei ollut ennusteellista merkitystä. Väitöskirjan tulokset osoittavat, että immunokemoterapiahoidetuilla DLBCL potilailla voidaan tunnistaa huonoennusteinen ei-itukeskusperäinen alatyyppi uudella immunohistokemiallisella algoritmilla. Lisäksi huonoennusteiseen taudinkuvaan viittaa BCL2 ilmentyminen. Taudin biologisista piirteistä tarvitaan silti täydentävää tietoa, ennen kuin nämä esitellyt tekijät voivat ohjata hoidon valintaa.
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    ABSTRACT: The BCL-6 gene, located on chromosome 3q27, is implicated in the normal germinal center formation and is frequently rearranged in a wide spectrum of lymphomas. However the links between genetic alterations and expression of the gene are not clearly determined. We established a quantitative RT-PCR assay based on TaqMan technology to quantify BCL-6 mRNA expression in different subtypes of lymphomas and to compare the level of expression in lymphomas characterized by the presence or absence of BCL-6 translocation. Total RNA was extracted from 105 nodes biopsies (35 diffuse large B cell lymphomas (DLBCL); 26 follicle center lymphomas (FCL); 7 marginal zone lymphomas (MZL); 6 mantle cell lymphomas (MCL); 6 chronic lymphocytic leukemia (CLL); 5 T cell lymphomas (TCL); 7 classical Hodgkin diseases (HD); 6 nodal metastasis (NM); and 7 reactive hyperplasia (RH)). BCL-6 gene rearrangement was assessed by Southern blot analysis in 75% of 3q27(+) DLBCL (n = 20) cases and 67% of 3q27(+) cases (n = 10). The highest level of relative BCL-6 expression was observed in FCL (9.12 +/- 7.28) comparatively to the other lymphoma subtypes including DLBCL (2.53 +/- 1.82; P < 0.001), MCL (1.23 +/- 0.73), MZL (1.49 +/- 1.3), HD (1.60 +/- 1.00), TCL (1.75 +/- 1.64), but also RH (3.91 +/- 3.12) or NM (1.95 +/- 2.6). Among the 26 FCL cases, we observed a lower expression in grade 3 (n = 8) than in grade 1/2 (P < 0.001). Conversely, we failed to show any difference between 3q27(+) DLBCL and 3q27(-)DLBCL cases (P = 0.42). Paradoxically BCL-6 expression in 3q27(+) FCL (n = 10) was significantly lower than in 3q27(-) FCL cases (P = 0.035). Finally, this study showed that BCL-6 expression in lymphoma is largely independent of chromosome 3q27 rearrangement and is more related to the histological subtype. Clinical implication and alternative deregulation pathways of BCL-6 expression remain to be determined.
    Leukemia 11/2002; 16(11):2318-25. DOI:10.1038/sj.leu.2402657 · 10.43 Impact Factor
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