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. 2016 Jan 19;7(3):2401-16.
doi: 10.18632/oncotarget.6262.

Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma

Qing Ye  1 , Zijun Y Xu-Monette  1 , Alexandar Tzankov  2 , Lijuan Deng  1 , Xiaoxiao Wang  1 , Ganiraju C Manyam  3 , Carlo Visco  4 , Santiago Montes-Moreno  5 , Li Zhang  3 , Karen Dybkær  6 , April Chiu  7 , Attilio Orazi  8 , Youli Zu  9 , Govind Bhagat  10 , Kristy L Richards  11 , Eric D Hsi  12 , William W L Choi  13 , J Han van Krieken  14 , Jooryung Huh  15 , Maurilio Ponzoni  16 , Andrés J M Ferreri  16 , Ben M Parsons  17 , Michael B Møller  18 , Miguel A Piris  5 , Jane N Winter  19 , L Jeffrey Medeiros  1 , Shimin Hu  1 , Ken H Young  1   20
Affiliations

Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma

Qing Ye et al. Oncotarget. .

Abstract

Double-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co-expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2- subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6- subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors.

Keywords: BCL2; BCL6; MYC; diffuse large B-cell lymphoma; double-hit.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Univariate analysis for patients with DLBCL with MYC, BCL2, and BCL6 rearrangemnts in the overall-, GCB, and ABC groups
A.-B., D.-E, G.-H. MYC and BCL2 rearrangements correlated with significantly poorer overall survival in overall and GCB- but not ABC-DLBCL. C., F., I. BCL6 translocation did not correlate with poorer overall survival.
Figure 2
Figure 2
A.-B. The prognostic significance of MYC rearrangements in DLBCL depends on BCL2 rearrangement. C.-D. BCL6 rearrangement had no additive effect to MYC rearrangements. E.-F. BCL6 translocation had no additive effect to BCL2 rearrangements. G.-H. MYC expression levels appeared to impact the survival of MYC+/BCL6+ rearranged DLBCL with marginal P values probably due to the small case numbers.
Figure 3
Figure 3
A.-B. Concurrent MYC/BCL2 rearrangements correlated with significant poorer overall survival. C.-D. Concurrent MYC+/BCL6+ rearrangements did not correlate with poorer overall survival. E.-F. Concurrent BCL2+/BCL6+ rearrangements did not correlate with poorer overall survival. G.-H. BCL6 attenuated the adverse prognostic impact of MYC+/BCL2+ double-hit lymphoma.
Figure 4
Figure 4. Univariate analysis for DLBCL patients with MYC, BCL2 and BCL6 protein expression in the overall-, GCB, and ABC-DLBCL
A.-B., D.-E., G.-H. MYC and BCL2 protein expression correlated with significantly poorer overall survival in overall, GCB- and ABC-DLBCL. C., F., I. BCL6 overexpression did not correlate with poor survival.
Figure 5
Figure 5
A., C., E. Patients with DLBCL and MYC/BCL2, BCL6/MYC or BCL2/BCL6 co-expression had significantly poorer overall survival in the DBLCL cohort. B. BCL2 overexpression had a synergetic effect with MYC overexpression and the adverse prognostic impact of MYC depended on BCL2 overexpression. D. BCL6 expression had no synergetic effect with MYC expression. F. BCL6 expression appeared to attenuate the adverse prognostic impact of BCL2 overexpression. G. The poorer overall survival of MYC+BCL6+ patients was due to the poor survival of MYC+BCL2+ patients. H. Isolated MYC+BCL6+ versus MYC+BCL2+ double-positive DLBCL had significantly better patient survival.
Figure 6
Figure 6. Gene expression signature for MYC/BCL2 double-hit DLBCL (A) and comparison of MYC+BCL2+ BCL6− versus MYC+BCL2−BCL6+ translocation in DLBCL (B)
See this image and copyright information in PMC

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