<i>MYC</i> translocation and an increased copy number predict poor prognosis in adult diffuse large B‐cell lymphoma (DLBCL), especially in germinal centre‐like B cell (GCB) type

Yoon, Sun Och; Jeon, Yoon Kyung; Paik, Jin Ho; Kim, W Y; Kim, Y A; Kim, J E; Kim, C W

doi:10.1111/j.1365-2559.2008.03076.x

Cited by 120 publications

(122 citation statements)

References 46 publications

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“…The PFS rates of t(14;18)-positive and t(14;18)-negative cases also differed significantly (P=0.044). These findings are similar to those previous reports, showing that t(14;18) negates the beneficial prognostic effect of the presence of the GCB phenotype [11] . However, another study reported that t(14;18) has no significant effects on OS or disease-free survival [14] .…”

Section: Discussionsupporting

confidence: 83%

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Clinical impact of t(14;18) in diffuse large B-cell lymphoma

Zhang

Cheng

Chen

et al. 2011

Chin. J. Cancer Res.

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Objective: Recent studies have suggested that t(14;18) is present in a significant proportion of diffuse large B-cell lymphomas (DLBCLs). However, the prognostic significance of this translocation and its relationship with BCL-2 protein expression remains controversial. Our study aimed to investigate the predictive power of t(14;18) and BCL-2 protein expression in the prognosis of DLBCLs.Methods: Biopsy specimens from 106 DLBCLs were analyzed using interphase fluorescence in situ hybridization (FISH). Immunophenotypic analysis of CD20, CD3, CD10, BCL-6, MUM1 and BCL-2 was performed by immunohistochemistry. SPSS 13.0 software was used for statistical analysis.Results: The t(14;18) was identified in 27 of 106 cases (25.5%). The percentages of tumor cells expressing CD10, BCL-6, MUM1 and BCL-2 were 21.7%, 26.4%, 56.6% and 73.6%, respectively. The presence of this translocation was significantly correlated with the expression of CD10 and immunophenotypic subtype (p＜0.001). No association was observed between BCL-2 protein expression and the presence of t(14;18). Multivariate analysis confirmed that both t(14;18) and BCL-2 expression were significantly associated with survival. Moreover, patients with t(14;18) had worse prognosis, compared with those with BCL-2 expression (for overall survival: hazard ratio, 4.235; 95%CI, p<0.001 vs. hazard ration, 2.743; 95%CI, p=0.011).Conclusions: The t(14;18) is a useful prognostic tool for the evaluation of DLBCL immunophenotype and prognosis. The prognosis of GCB (germinal centre-like B cell) DLBCL patients should be made with the consideration of the presence of this translocation, and the detection of t(14;18) should be included as a routine diagnostic test in these cases.

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Section: Discussionsupporting

confidence: 83%

“…The presence of t(14;18) may be important for the pathogenesis of DLBCL with t(14;18). However, the prognostic effect of this translocation and its relationship with BCL-2 protein expression remain controversial [10,11] .…”

Section: Introductionmentioning

confidence: 99%

Clinical impact of t(14;18) in diffuse large B-cell lymphoma

Zhang

Cheng

Chen

et al. 2011

Chin. J. Cancer Res.

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“…In the study by Yoon et al, 37 increased BCL2 copy number was identified in 17 of 145 (12%) cases and was associated with worse prognosis. In the 20 cases of MYC/BCL2 double-hit lymphoma reported by Snuderl et al, 15 one patient had MYC rearrangement with extra copies of BCL2 and had a poor prognosis.…”

Section: Discussionmentioning

confidence: 94%

“…All cases with BCL2 amplification demonstrated overexpression of BCL2 and were associated with a worse prognosis. Extra BCL2 copies were more commonly seen in the non-GCB type of DLBCL 37,39 and usually associated with overexpression of BCL2, 40 which has been correlated with poorer prognosis in DLBCL in some studies. 31 Overall, these studies directly or indirectly support the hypothesis that extra copies of MYC and BCL2 likely result in MYC and BCL2 overexpression in most cases and confer a poorer prognosis.…”

Section: Discussionmentioning

confidence: 99%

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Seegmiller

Lin

et al. 2015

Modern Pathology

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Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n ¼ 14) or more aggressive chemotherapy regimens (n ¼ 17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P ¼ 0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P ¼ 0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (Po0.01), less frequently expressed CD10 (Po0.01), and patients less often had an elevated serum lactate dehydrogenase level (P ¼ 0.01). In aggregate, these results support expanding the category of MYC/ BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations.

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“…Overall, these data confirm the Yoon et al findings that MYC translocation predicts poor prognosis, especially in GCB DLBCL. 28 …”

Section: Myc Translocations In Untreated Dlbcl Patientsmentioning

confidence: 99%

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

Gupta¹,

Maurer²,

Wellik³

et al. 2012

Blood

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35% of cases were pSTAT3-positive, and pSTAT3 positivity was more frequent in the non-GCB (P ‫؍‬ .06) type but did not correlate with event-free survival (EFS). Myc expression was observed in 50% of cases and was more frequent in non-GCB type (P ‫؍‬ .07). Myc-positive cases had inferior EFS in all patients, including the GCB and pSTAT3-positive cases, were more likely to express Myc (P ‫؍‬ .06). Myc translocations involving the major breakpoint regions were found in 10% (3 of 29) of cases, and all 3 cases were GCB and had an inferior EFS (P ‫؍‬ .09). pSTAT3, but not Myc expression, was correlated with elevated pretreatment serum cytokines, such as IL-10 (P ‫؍‬ .05), G-CSF (P ‫؍‬ .03), and TNF-␣ (P ‫؍‬ .04). pSTAT3 IHC in DLBCL tumors has the potential to identify patients for STAT3 pathway-directed therapy; Myc IHC is a potential marker for inferior EFS in GCB patients. (Blood. 2012; 120(22):4400-4406) IntroductionThe most significant advance in the treatment of diffuse large B-cell lymphoma (DLBCL) over the past 15 years has been the addition of rituximab to standard CHOP chemotherapy (R-CHOP). [1][2][3] We recently demonstrated in a phase 2 study (N0489; www.clinicaltrials.gov, #NCT00301821) that the anti-CD22 monoclonal antibody epratuzumab can be successfully added to R-CHOP (ER-CHOP) without additional toxicity and with potentially improved survival parameters. 4 Despite these advances, 30%-40% of patients still relapse and die of disease. Current pathology practice classifies DLBCL into at least 3 distinct subtypes: germinal center B cell-like (GCB), activated B cell-like (ABC), and primary mediastinal B-cell lymphoma by gene expression profiling or immunohistochemistry (IHC). 5,6 These classifications are being evaluated in new DLBCL trials, and there have been some reports suggesting that agents, such as bortezomib and lenalidomide, are more effective in non-GCB type DLBCL. 7,8 To improve outcomes for DLBCL patients, it is necessary to identify additional novel targets within GCB and non-GCB classifications to further stratify patients for prognosis and assist in choosing therapy for the individual patient.Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor that resides in the cytoplasm. 9 Phosphorylation of STAT3 (pSTAT3) at its Tyr-705 residue (pSTAT3 Tyr705 ) leads to activation and translocation to the nucleus where pSTAT3 regulates several target genes, such as MYC. 10,11 Constitutively active STATs (particularly STAT3 and STAT5) contribute to the malignant phenotype in both human cancer cell lines and primary tumors. 12,13 Recently, it has been reported that STAT3 is overexpressed in ABC-type DLBCL human cell lines. 14,15 The role of pSTAT3 as a prognostic factor in DLBCL patients treated with R-CHOP-based therapies is unknown.Translocations involving the MYC gene at 8q24 are associated with Burkitt lymphoma. 16 Moreover, MYC translocations have been reported to occur in DLBCL with a frequency of 5%-10%. [17][18][19] Myc protein can be expressed ...

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MYC translocation and an increased copy number predict poor prognosis in adult diffuse large B‐cell lymphoma (DLBCL), especially in germinal centre‐like B cell (GCB) type

Abstract: Analyses of MYC and Bcl-2 status, i.e. translocation and ICN, in the context of DLBCL phenotype might help predict prognosis and determine therapeutic strategies.

Cited by 120 publications

References 46 publications

Clinical impact of t(14;18) in diffuse large B-cell lymphoma

Clinical impact of t(14;18) in diffuse large B-cell lymphoma

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Expression of Myc, but not pSTAT3, is an adverse prognostic factor for diffuse large B-cell lymphoma treated with epratuzumab/R-CHOP

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