Comprehensive Genomic Profiling of EBV-Positive Diffuse Large B-cell Lymphoma and the Expression and Clinicopathological Correlations of Some Related Genes.

Yangying Zhou,Can Lu,Weiping Su,Meizuo Zhong,Wei Liu,Huan Liu,Jianhua Zhou,Wei Lin,Yuanliang Yan,Yumei Duan,Hong Zhu,Li Liu,Zhijie Xu

doi:10.3389/fonc.2019.00683

Abstract

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is a rare type of lymphoma with a high incidence in elderly patients, poor drug response, and unfavorable prognosis. Despite advances in genomic profiling and precision medicine in DLBCL, EBV+ DLBCL remain poorly characterized and understood. We include 236 DLBCL patients for EBV-encoded mRNA (EBER) in situ hybridization detection and analyzed 9 EBV+ and 6 EBV negative cases by next-generation sequencing (NGS). We then performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) to analyze chromosome rearrangements and gene expressions in 22 EBV+ and 30 EBV negative cases. The EBER results showed a 9.3% (22/236) positive rate. The NGS results revealed recurrent alterations in MYC and RHOA, components of apoptosis and NF-κB pathways. The most frequently mutated genes in EBV+ DLBCL were MYC (3/9; 33.3%), RHOA (3/9; 33.3%), PIM1 (2/9; 22.2%), MEF2B (2/9; 22.2%), MYD88 (2/9; 22.2%), and CD79B (2/9; 22.2%) compared with KMT2D (4/6; 66.7%), CREBBP (3/6; 50.0%), PIM1 (2/6; 33.3%), TNFAIP3 (2/6; 33.3%), and BCL2 (2/6; 33.3%) in EBV-negative DLBCL. MYC and KMT2D alterations stood out the most differently mutated genes between the two groups. FISH detection displayed a lower rearrangement rate in EBV+ cohort. Furthermore, KMT2D expression was highly expressed and associated with poor survival in both cohorts. MYC was only overexpressed and related to an inferior prognosis in the EBV+ DLBCL cohort. In summary, we depicted a distinct mutation profile for EBV+ and EBV-negative DLBCL and validated the differential expression of KMT2D and MYC with potential prognostic influence, thereby providing new perspectives into the pathogenesis and precision medicine of DLBCL.

Highlights

Epstein–Barr virus-positive (EBV+) diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS), is a new and rare type of DLBCL according to the 2016 WHO lymphoma classification, with clinically highly aggressiveness and no history of immunosuppression
We explored that with age over 60, KMT2D, PIM1, and CREBBP were frequently mutated in Epstein-Barr virus (EBV)-negative patients, while MYD88, ID3, and FOXO1 highly altered in EBV+ DLBCL group
We found that RHOA and MYC were pre-dominantly mutated in the EBV+ DLBCL cases with nodal invasive (Figure 1A)

Summary

Introduction

Epstein–Barr virus-positive (EBV+) diffuse large B cell lymphoma (DLBCL), not otherwise specified (NOS), is a new and rare type of DLBCL according to the 2016 WHO lymphoma classification, with clinically highly aggressiveness and no history of immunosuppression. Patients frequently present with extranodal involvement, and more than half had advanced disease with high International Prognostic Index (IPI) scores. These patients showed a poor response to the conventional R-CHOP (anti-CD20 monoclonal antibodyrituximab, combined with cyclophosphamide, vincristine doxorubicin, and prednisone) regimen, with an inferior survival rate of ∼24 months [2, 9, 10]

Methods

Results

Conclusion