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: 2.66). 02/2002; 20(1):161-5. DOI: 10.3892/ijo.20.1.161
Source: PubMed

ABSTRACT 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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    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: Diffuse Large B cell lymphoma (DLBCL) is characterized by a markedly heterogeneous clinical course and response to therapy that is not appreciated with standard histopathologic and immunophenotypic evaluations. Analysis of global gene expression using DNA microarrays has the potential to improve the classification of lymphomas. Molecular profiling may allow the description of specific disease subtypes with similar clinical behavior and outcome. In addition, gene expression profiling has led to the discovery of new putative genes and a better understanding of aberrant signaling pathways. These insights may lead to the discovery of new targeted therapies. This review describes the progress that has been made in our understanding of DLBCL as a result of gene expression profiling.
    Leukemia and Lymphoma 05/2007; 48(4):669-82. · 2.61 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. We analyzed 100 cases of DLBCL to evaluate the prognostic value of immunohistochemical markers derived from the gene expression profiling-defined cell origin signature, including MYC, BCL2, BCL6, and FOXP1 protein expression. We also investigated genetic alterations in BCL2, BCL6, MYC and FOXP1 using fluorescence in situ hybridization and assessed their prognostic significance. BCL6 rearrangements were detected in 29% of cases, and BCL6 gene alteration (rearrangement and/or amplification) was associated with the non-germinal center B subtype (non-GCB). BCL2 translocation was associated with the GCB phenotype, and BCL2 protein expression was associated with the translocation and/or amplification of 18q21. MYC rearrangements were detected in 15% of cases, and MYC protein expression was observed in 29% of cases. FOXP1 expression, mainly of the non-GCB subtype, was demonstrated in 37% of cases. Co-expression of the MYC and BCL2 proteins, with non-GCB subtype predominance, was observed in 21% of cases. We detected an association between high FOXP1 expression and a high proliferation rate as well as a significant positive correlation between MYC overexpression and FOXP1 overexpression. MYC, BCL2 and FOXP1 expression were significant predictors of overall survival. The co-expression of MYC and BCL2 confers a poorer clinical outcome than MYC or BCL2 expression alone, whereas cases negative for both markers had the best outcomes. Our study confirms that DLBCL, characterized by the co-expression of MYC and BCL2 proteins, has a poor prognosis and establishes a significant positive correlation with MYC and FOXP1 over-expression in this entity.
    PLoS ONE 01/2014; 9(6):e98169. · 3.53 Impact Factor