Prognostic Significance of <i>MYC</i> Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium

Rosenwald, Andreas; Bens, Susanne; Advani, Ranjana H.; Barrans, Sharon; Copie‐Bergman, Christiane; Elsensohn, Mad-Hélénie; Natkunam, Yasodha; Calaminici, Maria; Sander, Birgitta; Baia, Maryse; Smith, Alexandra; Painter, Daniel; Pham, Luu Q.; Song, Zhao; Ziepert, Marita; Jordanova, Ekaterina S.; Molina, Thierry Jo; Kersten, Marie José; Kimby, Eva; Klapper, Wolfram; Raemaekers, John; Schmitz, Norbert; Jardin, Fabrice; Stevens, Wendy B C; Hoster, Eva; Hagenbeek, Anton; Gribben, John G.; Siebert, Reiner; Gascoyne, Randy D.; Scott, David W.; Gaulard, Philippe; Salles, Gilles; Burton, Catherine; Jong, Daphne de; Sehn, Laurie H.; Maucort‐Boulch, Delphine

doi:10.1200/jco.19.00743

Cited by 173 publications

(169 citation statements)

References 36 publications

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“…This could potentially explain in part the variability (20-100%) of MYC protein expression in tumour cells of MYC translocation positive DLBCL [50]. The above findings are also consistent with the observation that the adverse prognosis of the MYC/BCL2-DH group is primarily due to those with IG as MYC translocation partner [48,51].…”

Section: Discussionsupporting

confidence: 86%

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

et al. 2019

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Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.

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Section: Discussionsupporting

confidence: 86%

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

et al. 2019

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“…In multivariate Cox regression modeling, MYC rearrangement was predictive of inferior survival and provided prognostic information independent of IPI score or stage for both OS and EFS . In a recent report from the Lunenburg Lymphoma Biomarker Consortium, MYC ‐R was associated with a significantly shorter PFS and OS, with a strong time‐dependent effect within the first 24 months after diagnosis; interestingly, the adverse prognostic impact of MYC ‐R in that study was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner. In this current study, DLBCL patients with MYC rearrangement had significant poorer survival than those without MYC rearrangement in all patients and in the subgroup of GCB DLBCL patients, and MYC ‐R was an independent poor prognostic factor for OS in DLBCL patients by multivariate analysis.…”

Section: Discussionmentioning

confidence: 73%

“…5,23,[25][26][27][28][29][30][31] In multivariate Cox regression modeling, MYC rearrangement was predictive of inferior survival and provided prognostic information independent of IPI score or stage for both OS and EFS. 26,32 In a recent report from the Lunenburg Lymphoma Biomarker Consortium, 33 with t(14;18) had a significantly worse survival compared with those without the translocation. 37 A recent study showed that isolated BCL2 translocation was not predictive of outcome in the DLBCL patients as a whole, but did predict outcome in those with GCB type: Therefore, MYC/BCL2 DE is much more common than DHL.…”

Section: Discussionmentioning

confidence: 99%

MYC rearrangement and MYC/BCL2 double expression but not cell‐of‐origin predict prognosis in R‐CHOP treated diffuse large B‐cell lymphoma

Liu

Medeiros

et al. 2020

European J of Haematology

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Objective Diffuse large B‐cell lymphoma (DLBCL) can be classified as germinal center B cell–like (GCB) or activated B cell–like (ABC)/non‐GCB based on cell‐of‐origin (COO) classification. This study evaluated the prognostic significance of COO classification in 250 patients diagnosed with de novo DLBCL who received R‐CHOP therapy. We also assessed whether the genomic status of MYC, BCL2, or MYC/BCL2 double expression (DE) could provide additional prognostic information for DLBCL patients. Methods The clinicopathologic features and outcome of patients with GCB DLBCL were compared to patients with non‐GCB DLBCL using Fisher's exact test. The prognostic significance of COO, MYC‐R, and MYC/BCL2 DE were studied using multivariate Cox proportional hazard analysis. Results There were 162 men and 88 women with a median age of 62 years (range, 18‐86). Forty‐five of 250 (18%) cases harbored MYC rearrangement (R). The frequency of MYC‐R was much higher in GCB than in non‐GCB tumors (40/165, 24% vs 5/85, 6%) (P = .0001). MYC/BCL2 DE was observed in 53 of 125 (42%) cases. COO classification failed to predict overall survival (OS) in DLBCL patients, either those patients with MYC‐R were included (P = .10) or not (P = .27). In contrast, MYC‐R and MYC/BCL2 DE significantly correlated with inferior OS (P = .0001 and P = .001, respectively). In multivariate analysis, MYC‐R and MYC/BCL2 DE were still independent prognostic factors in DLBCL patients. Conclusions MYC‐R and MYC/BCL2 DE are independent prognostic factors for DLBCL patients treated with R‐CHOP. In this cohort, COO classification failed to stratify patient outcome.

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“…Hence, we are unable to comment on the impact of the translocation partner for MYC, although there is emerging evidence that the negative prognostic impact of MYC-R in DLBCL is largely observed in patients in whom MYC is translocated to an immunoglobulin partner. 26,27 Lastly, immunohistochemistry data for MYC expression and BCL2 expression was missing or inconclusive in 61% and 32% of patients, respectively, hence a reliable analysis of the differences in outcomes between doubleexpressor and non-double-expressor DLBCL/HGBL could not be performed.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics

et al. 2020

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There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.

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Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium

Cited by 173 publications

References 36 publications

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

MYC rearrangement and MYC/BCL2 double expression but not cell‐of‐origin predict prognosis in R‐CHOP treated diffuse large B‐cell lymphoma

Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics

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