Comparison of genomic alterations in Epstein–Barr virus‐positive and Epstein–Barr virus‐negative diffuse large B‐cell lymphoma

Abstract

Abstract Background Epstein–Barr virus (EBV)‐positive diffuse large B‐cell lymphoma (EBV‐posDLBCL) is an aggressive B‐cell lymphoma that often presents similar morphological and immune phenotype features to that of EBV‐negative DLBCL (EBV‐negDLBCL). Aims and Methods To better understand their difference in genomic landscape, we performed whole‐exome sequencing (WES) of EBV‐posDLBCL and EBV‐negDLBCL. Results This analysis revealed a new mutational signature 17 (unknown) and signature 29 (smoking) in EBV‐posDLBCL as well as a specific mutational signature 24 (associated with aflatoxin) in EBV‐negDLBCL. Compared with EBV‐negDLBCL, more somatic copy number alterations (CNAs) and deletions were detected in EBV‐posDLBCL (p = 0.01). The most frequent CNAs specifically detected in EBV‐posDLBCL were gains at 9p24.1 (PDL1 and JAK2), 8q22.2‐q24.23 (DEPTOR and MYC), and 7q31.31‐q32.2 (MET), which were validated in additional EBV‐posDLBCL cases. Overall, 53.7% (22/41) and 62.9% (22/35) of the cases expressed PD‐L1 and c‐MET, respectively, in neoplastic cells, whereas only 15.4% (4/26) expressed c‐MYC. Neoplastic c‐MET expression was positively correlated with PD‐L1 (p < 0.001) and MYC expression (p = 0.016). However, EBV‐posDLBCL cases did not show any differences in overall survival between PD‐L1‐, c‐MET‐, or c‐MYC‐positive and ‐negative cases or between age‐related groups. Analysis of the association between somatic mutation load and EBV status showed no difference in the distribution of tumor mutant burden between the two lymphomas (p = 0.41). Recurrent mutations in EBV‐posDLBCL implicated several genes, including DCAF8L1, KLF2, and NOL9, while in EBV‐negDLBCL, ANK2, BPTF, and CNIH3 were more frequently mutated. Additionally, PIM1 is the most altered gene in all the WES‐detected cases. Conclusions Our results confirm that genomic alteration differs significantly between EBV‐posDLBCL and EBV‐negDLBCL, and reveal new genetic alterations in EBV‐posDLBCL. The positive correlation of c‐MET and PD‐L1/c‐Myc expression may be involved in the pathogenesis of EBV‐posDLBCL, which is should be explored prospectively in trials involving MET‐directed therapies.

Keywords

• diffuse large B‐cell lymphoma
• Epstein–Barr virus (EBV)
• genetic features
• PD‐L1/MET amplification
• somatic mutation
• whole exome sequencing