Oncogenic Mutations and Tumor Microenvironment Alterations of Older Patients With Diffuse Large B-Cell Lymphoma

Abstract

The incidence of diffuse large B-cell lymphoma (DLBCL) increases by age and older DLBCL are commonly related to poor prognosis. However, the clinical and biological features of older DLBCL patients remain to be determined. A total of 2,445 patients with newly diagnosed DLBCL were enrolled for clinical data analysis according to age at diagnosis, with tumor samples of 1,150 patients assessed by DNA sequencing and 385 patients by RNA sequencing. Older DLBCL presented advanced disease stage, elevated serum lactate dehydrogenase, poor performance status, multiple extranodal involvement, high percentage of double expressor subtype, and adverse clinical outcome. According to molecular features, age was positively correlated with the oncogenic mutations of PIM1, MYD88, BTG2, CD79B, TET2, BTG1, CREBBP, TBL1XR1, and with the MYD88-like genetic subtype. These oncogenic mutations were involved in B-cell receptor/NF-κB signaling, B-cell differentiation, and histone acetylation based on biological functions. Older DLBCL also manifested reduction in CD4+ naïve T and CD8+ naïve T cells, and also increased recruitment of exhausted T cells and macrophages, leading to immunosuppressive tumor microenvironment. Our work thus contributes to the understanding of aging-related oncogenic mutations and tumor microenvironment alterations in lymphoma progression, and may provide new insights to mechanism-based targeted therapy in DLBCL.

Biological signatures of the International Prognostic Index in diffuse large B-cell lymphoma

“…Specific oncogenic mutations are linked to DLBCL progression. 1 , 14 , 16 As revealed by DNA sequencing, mutations involving the BCR/NF-κB signaling pathway, B-cell differentiation, and histone acetylation (such as BTG1 , CD79B , FAS , MYD88 , MYD88 L265P , TBL1XR1 , and TET2 ) showed significant association with age, consistent with our previous study. 14 Multiple extranodal involvement was often related to the MCD subtype, with increased prevalence of MYD88 L265P and CD79B mutations.…”

“… 1 , 14 , 16 As revealed by DNA sequencing, mutations involving the BCR/NF-κB signaling pathway, B-cell differentiation, and histone acetylation (such as BTG1 , CD79B , FAS , MYD88 , MYD88 L265P , TBL1XR1 , and TET2 ) showed significant association with age, consistent with our previous study. 14 Multiple extranodal involvement was often related to the MCD subtype, with increased prevalence of MYD88 L265P and CD79B mutations. 16 Elevated LDH represents tumor growth and invasive potential, 28 co-occurring with unfavorable markers, such as TP53 mutation, 29 and BCR/NF-κB–associated mutations (such as BTG1 , CD79B , MYD88 , and PRDM1 ).…”

“…BCL2 , BCL6 , and MYC translocations were performed on paraffin sections with cutoff values as 10%. 14 , 15 …”

“…Variants were filtered according to the rules listed in our previous studies. 14 , 15 , 19 Details for DNA sequencing are provided in the supplementary material.…”

Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study

“…3,4 Importantly, older patients also present with immunophenotypic and genetic features, such as activated B-cell subtype, BCL-2 overexpression, MYD88 and CD79B mutations, and a continuous increase in genetic complexity with age. 4,5 The Comprehensive Geriatric Assessment (CGA), based on age, comorbidities, and functional abilities of daily living, categorises patients into fit, unfit, or frail, for older patients with DLBCL, to choose the best treatment approaches. [6][7][8][9][10][11] Usually, older unfit or frail patients are excluded from large clinical trials and the optimal treatment for this population is still not clear.…”