TET2 and LILRB1 mutations are frequent in Epstein–Barr virus‐positive diffuse large B‐cell lymphoma especially in elderly patients

Abstract

Background Diffuse large B‐cell lymphoma (DLBCL) harboring Epstein–Barr virus (EBV) primarily occurs in patients who have underlying immunodeficiency or in elderly patients but is also reported in young, immunocompetent patients. The authors investigated the pathologic differences in EBV‐positive DLBCL in these three groups of patients. Methods In total, 57 patients with EBV‐positive DLBCL were included in the study; of these, 16 patients had associated immunodeficiency, 10 were young (younger than 50 years), and 31 were elderly (aged 50 years or older). Immunostaining for CD8, CD68, PD‐L1, and EBV nuclear antigen 2, and panel‐based next‐generation sequencing was performed on formalin‐fixed, paraffin‐embedded blocks. Results Immunohistochemistry revealed EBV nuclear antigen 2 positivity in 21 of the 49 patients. The degree of CD8‐positive and CD68‐positive immune cell infiltration and PD‐L1 expression did not differ significantly in each group. Extranodal site involvement was more common in young patients (p = .021). In mutational analysis, the genes with the highest mutation frequency were PCLO (n = 14), TET2 (n = 10), and LILRB1 (n = 10). For the TET2 gene, all 10 mutations were found in elderly patients (p = .007). Compared with a validation cohort, both TET2 and LILRB1 showed a higher mutation frequency in EBV‐positive patients than in EBV‐negative patients. Conclusions EBV‐positive DLBCL occurring in three different age and immune status groups showed similar pathologic characteristics. Notably, a high frequency of TET2 and LILRB1 mutations was characteristic of this disease in elderly patients. Further studies are needed to determine the role of TET2 and LILRB1 mutations in the development of EBV‐positive DLBCL along with immune senescence. Plain Language Summary Epstein–Barr virus‐positive diffuse large B‐cell lymphoma occurring in three different groups (immunodeficiency‐associated, young, and elderly) showed similar pathologic characteristics. The frequency of TET2 and LILRB1 mutations was high in elderly patients with Epstein–Barr virus‐positive diffuse large B‐cell lymphoma.

The biology and treatment of Epstein-Barr virus-positive diffuse large B cell lymphoma, NOS

“…However, in vivo studies have shown that the expression of LMP1 or LMP2A alone cannot lead to malignant transformation of B cells, and the activity of BTK pathway in EBV+DLBCL-NOS tumor cells is significantly down-regulated [ 26 ]. A large number of pathogenic mutations were also detected in EBV+DLBCL-NOS ( Table 2 ) [ 9 , 27 , 28 ]. For example, Liu et al analyzed 11 Chinese patients with EBV+DLBCL-NOS using whole exome sequencing [ 7 ].…”

Metabolic Barriers in Cancer and Cancer Therapy

“…Therefore, blockade of the PD-1/PD-L1 axis may enhance an antitumor immunity of both adaptive and innate mechanisms. Of note, the receptors PD-1, LILRB1, and SIRPa all contain an immunoreceptor tyrosine-based inhibitory motif domain, which may be instrumental for downstream signals that inhibit phagocytosis (258, 259,274,276,277). Based on this, in studies aimed at monitoring response in patients with cancer undergoing treatment with immune checkpoint inhibitors, researchers should consider the myeloid compartment as a potential target and predictive biomarker (104,160).…”

The cross-talk between macrophages and tumor cells as a target for cancer treatment

“…Of note, the receptors PD-1, LILRB1, and SIRPα all contain an immunoreceptor tyrosine-based inhibitory motif domain, which may be instrumental for downstream signals that inhibit phagocytosis ( 258 , 259 , 274 , 276 , 277 ). Based on this, in studies aimed at monitoring response in patients with cancer undergoing treatment with immune checkpoint inhibitors, researchers should consider the myeloid compartment as a potential target and predictive biomarker ( 104 , 160 ).…”