Clinical Relevance of BCL2, BCL6, and MYC Rearrangements in Diffuse Large B-Cell Lymphoma

Krámer, M; Hermans, Jos; Wijburg, E.; Philippo, Katja; Geelen, Eric; Krieken, J.H.J.M. van; Jong, Daphne de; Maartense, E.; Schuuring, Ed; Kluin, Philip M.

doi:10.1182/blood.v92.9.3152.421a07_3152_3162

Cited by 76 publications

(77 citation statements)

References 48 publications

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“…Kramer et al reported that 7 of the 10 patients with DLBCL with c-MYC had an extranodal lesion, and five of them were gastrointestinal tract lesions. (12) It is thought that their results are similar to those of the present report.…”

Section: Discussionsupporting

confidence: 92%

Clinical significance of 8q24/c‐MYC translocation in diffuse large B‐cell lymphoma

Niitsu

Okamoto²,

Miura³

et al. 2009

Cancer Science

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Diffuse large B-cell lymphoma (DLBCL) has heterogeneous clinical, histological, and molecular features. We evaluated the clinical characteristics and prognoses of patients with DLBCL carrying 8q24 translocations. A total of 1864 consecutive patients with nonHodgkin's lymphoma were treated in the Adult Lymphoma Treatment Study Group from 1998 to 2005. Of the 252 patients with DLBCL with abnormal karyotypes, 28 patients with DLBCL with the 8q24 translocation were identified. There were 14 men and 14 women, with a median age of 61 years. The 8q24 translocation was observed significantly more frequently among patients with poor performance status, among patients with high lactate dehydrogenase level, and among patients with bone marrow involvement. The 5-year overall survival was 43.9% among the patients with 8q24 translocation, and 67% among the patients with other chromosomal abnormalities. The 8q24 translocation group showed significantly poorer prognosis than the group with other translocations. In addition, patients with t(14;18) and 8q24 translocation showed significantly poorer prognosis than those with 8q24 translocation alone. It will be necessary to study whether more aggressive chemotherapy or rituximab combination chemotherapy is effective in 8q24 translocation cases. (Cancer Sci 2009; 100: 233-237) D iffuse large B-cell lymphoma (DLBCL) accounts for approximately 50% of non-Hodgkin's lymphomas (NHL) and has heterogeneous clinical, histological, immunophenotypic, cytogenetic, and molecular features. Currently, the international prognostic index (IPI) is widely used as a prognostic factor.(1) However, it has been established that clinical features and treatment responses are also dependent on genetic and molecular features that modify disease aggressiveness. The c-MYC gene at 8q24 is involved in three translocations, most commonly t(8;14) (q24;q32), and less often t(2;8) (p12;q24) and t(8;22) (q24;q11).(2) Overexpression of c-MYC drives cell proliferation and the expression of other genes involved in cell growth.(3) C-MYC translocation is characteristic of Burkitt lymphoma; t(8;14) occurs in 80 -90% of Burkitt lymphoma cases, and in up to 5-10% of DLBCL cases.(4) C-MYC activates genes that promote cell-cycle progression and suppresses inhibitory proteins like p21CIP1 and p27KIP1.(5) Paradoxically, c-MYC also promotes apoptosis via the p19ARF-p53 apoptotic pathway.(5) c-MYC appears to be more commonly found in DLBCL with extranodal involvement and associated with a more aggressive clinical course. The relationship between 8q24/c-MYC translocation and the clinical outcome of DLBCL has been the subject of controversy. We therefore studied the clinical characteristics of DLBCL with 8q24/c-MYC translocation and correlated the findings with clinical outcome. Patients and MethodsPatients. A total of 1543 consecutive patients with NHL were treated in the Adult Lymphoma Treatment Study Group (ALTSG) in Japan from 1998 to 2005. Chromosomal data were available for 489 (58%) of the 842 patients with DLBCL. Among t...

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Section: Discussionsupporting

confidence: 92%

Clinical significance of 8q24/c‐MYC translocation in diffuse large B‐cell lymphoma

Niitsu

Okamoto²,

Miura³

et al. 2009

Cancer Science

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“…(D) Kaplan-Meier survival curve showing that the four variables, IPI ‡ 2, rearranged 3q27, > 50% BCL2 expression and lack of a GC phenotype, have an additive adverse prognostic effect. Each patient was ÔscoredÕ according to the presence or absence of each factor, giving scores of 0, 1, 2, 3 and 4. or no effect Pescarmona et al, 1997;Kramer et al, 1998;Vitolo et al, 1998). An explanation for the reported favourable outcome of patients with 3q27 rearrangements, in some studies, is the inclusion of significant numbers of patients with extranodal disease.…”

Section: Discussionmentioning

confidence: 97%

“…Primary extranodal DLBCL are, by definition, early stage, often localized, low-bulk tumours that are associated with a more favourable prognosis. BCL6 gene rearrangements are reported to occur more frequently in extranodal disease than in primary nodal disease Muramatsu et al, 1996Muramatsu et al, , 1997Liang et al, 1997a;Kramer et al, 1998), and inclusion of a significant number of extranodal lymphomas could mask the effect of the rearrangement on OS. In contrast, the present series consists entirely of a pure cohort of presentation cases of nodal DLBCL.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is no consensus on the effect of BCL6 gene rearrangements on patient outcome. Previous studies have reported a favourable prognosis ), no effect Pescarmona et al, 1997;Kramer et al, 1998;Vitolo et al, 1998) or a poor outcome (Muramatsu et al, 1996;Ichinohasama et al, 1998;Akasaka et al, 2000), and an association with aggressive disease has also been noted (Vitolo et al, 1998).…”

mentioning

confidence: 93%

“…The BCL2 protein is expressed in a significant proportion of DLBCLs, either as a consequence of, or independently of, the t(14;18) (Hill et al, 1996;Gascoyne et al, 1997). This has been shown in a number of studies to have an adverse effect on survival (Hill et al, 1996;Gascoyne et al, 1997;Martinka et al, 1997;Kramer et al, 1998) and is the most widely accepted cellular prognostic factor. There remains uncertainty as to the prognostic significance of other cellular variables such as specific morphological subtypes, cell cycle fraction, and abnormalities of p53, all of which have been shown in some studies to affect outcome.…”

mentioning

confidence: 99%

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Rearrangement of the BCL6 locus at 3q27 is an independent poor prognostic factor in nodal diffuse large B‐cell lymphoma

et al. 2002

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Summary. Diffuse large B-cell lymphomas (DLBCL) are a heterogeneous group of tumours, varying in clinical features, immunophenotype and cytogenetics. The aim of this study was to investigate the prognostic significance of BCL6 gene rearrangement at the 3q27 locus in patients with primary nodal disease, and to examine interrelationships with immunophenotype and International Prognostic Index (IPI). We have developed a fluorescent in situ hybridization (FISH)-based technique for the retrospective analysis of the effect of BCL6 gene rearrangements on survival, using nuclei extracted from paraffin-embedded tissue. FISH results were obtained in 111 presentation cases of nodal DLBCL. The IPI was calculated and each case was stained immunocytochemically for BCL6, BCL2 and CD10. 3q27 rearrangements were detected in 25% of cases. BCL2 protein and a germinal centre (GC) phenotype (defined as CD10 + , BCL6 + ) were expressed in 56% and 41% of cases respectively. In multivariate analysis, rearrangement of 3q27 and BCL2 expression and the absence of a GC phenotype were associated with a poor prognosis. These factors can be used in conjunction with the IPI to improve risk stratification in nodal DLBCL.

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Interphase FISH detection of BCL2 rearrangement in follicular lymphoma using breakpoint‐flanking probes

Vaandrager

Schuuring

Raap

et al. 2000

Genes Chromosom. Cancer

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Rearrangement of the BCL2 gene is an important parameter for the differential diagnosis of non-Hodgkin lymphomas. Although a relatively large proportion of breakpoints is clustered, many are missed by standard PCR. A FISH assay is therefore desired. Up to now, a lack of probes flanking the BCL2 gene has limited the possibilities for a FISH assay to an approach based on colocalization of probes for BCL2 and the immunoglobulin heavy chain (IGH) locus. Intrinsically high rates of false positive nuclei and high interobserver variability make such assays unsuitable for use on lymphoma tissue samples, where tumor cells often form only a minority of the cell population. Using YAC end cloning techniques and screening of a PAC library, we have isolated PAC clones flanking the BCL2 gene. Using these PACs, and several cosmid clones in the second BCL2 intron, we developed a segregation-based interphase FISH assay with two probe combinations enabling separate detection of 5' and 3' (mbr/mcr) breakpoints. The assay was applied to a series of 40 follicular lymphomas. To evaluate the results, the same lymphomas were analyzed by DNA fiber FISH with a 600-kb set of BCL2 DNA clones labeled in alternating colors in combination with a color barcode covering the IGH locus. This approach allowed precise mapping of BCL2 breakpoints, and simultaneously showed juxtaposition of IGH genes to BCL2. Comparison of the results of interphase and fiber FISH showed complete correlation. Five cases were negative with both FISH techniques as well as with Southern blotting. Interestingly, all of these 5 cases lacked BCL2 overexpression as determined by immunohistochemistry, against 3 of 35 rearrangement-positive follicular lymphomas. Furthermore, absence of t(14;18) seemed to be correlated with a higher histologic grade (grades 2 and 3 according to Berard). These data indicate that the segregation-based interphase FISH assay detects 100% of BCL2 rearrangements. Because interpretation of the results is straightforward and requires no extensive experience, this assay may be the best available diagnostic test for BCL2 rearrangement. Genes Chromosomes Cancer 27:85-94, 2000.

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Clinical Relevance of BCL2, BCL6, and MYC Rearrangements in Diffuse Large B-Cell Lymphoma

Cited by 76 publications

References 48 publications

Clinical significance of 8q24/c‐MYC translocation in diffuse large B‐cell lymphoma

Clinical significance of 8q24/c‐MYC translocation in diffuse large B‐cell lymphoma

Rearrangement of the BCL6 locus at 3q27 is an independent poor prognostic factor in nodal diffuse large B‐cell lymphoma

Interphase FISH detection of BCL2 rearrangement in follicular lymphoma using breakpoint‐flanking probes

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