Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B‐cell lymphoma. Issue 7 (24th November 2020)

• Record Type: Journal Article
• Authors: Shen, Rong; Xu, Peng‐Peng; Wang, Nan; Yi, Hong‐Mei; Dong, Lei; Fu, Di; Huang, Jin‐Yan; Huang, Heng‐Ye; Janin, Anne; Cheng, Shu; Wang, Li; Zhao, Wei‐Li
• Is Part Of: Clinical and translational medicine. Volume 10:Issue 7(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-11-24
• Subjects: diffuse large B‐cell lymphoma -- extracellular matrix -- extranodal invasion -- MYD88 -- oncogenic mutation -- regulatory T cells -- tumor microenvironment; Clinical medicine -- Periodicals; Medicine, Experimental -- Periodicals; Medical innovations -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 616.027
• DOI: 10.1002/ctm2.221
• Languages: English
• ISSNs: 2001-1326

Abstract

Abstract: Background: Diffuse large B‐cell lymphoma (DLBCL) is an aggressive subtype of lymphoma, and multiple extranodal involvement (ENI) indicates adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on ENI in DLBCL. Methods: The clinical features of 1960 patients with newly diagnosed DLBCL were analyzed, and DNA and RNA sequencing was performed on 670 and 349 patients, respectively. Oncogenic mutations and tumor microenvironment alterations were compared according to ENI and evaluated in zebrafish patient‐derived tumor xenograft models. Results: Multiple ENI was significantly associated with poor performance status, advanced stage, elevated serum lactate dehydrogenase, low response rate, and inferior prognosis. Lymphoma invasion of the bones, spleen, bone marrow, liver, and central nervous system were independent unfavorable prognostic factors. MYD88 was frequently mutated in patients with multiple ENI, co‐occurred with mutations in CD79B, PIM1, TBL1XR1, BTG1, MPEG1, and PRDM1, and correlated with invasion of the bones, kidney/adrenal glands, breasts, testes, skin, and uterus/ovaries. For tumor microenvironment alterations, patients with multiple ENI showed higher regulatory T‐cell (Treg)‐recruiting activity, but lower extracellular matrix‐encoding gene expression, than those without ENI and with single ENI. Elevated Treg‐recruiting activity was related to mutations in B2M, SGK1, FOXO1, HIST1H1E, and ARID1A, and correlated with invasion of the bone marrow and thyroid. Additionally, mutations in MYD88, PIM1, TBL1XR1, SGK1, FOXO1, HIST1H1E, and ARID1A were associated with decreased major histocompatibility complex class I expression. Zebrafish models further revealed relationships between MYD88 mutations and invasion of the kidneys and gonads, as well as B2M mutations and invasion of the bone marrow. Increased CXCR4 expression is linked to bone marrow invasion in an organotropic way. Conclusions: Our findings thus contribute to an improved understanding of the biological behavior of multiple ENI and provide a clinical rationale for targeting ENI in DLBCL. Abstract : 1. DLBCL patients with multiple extranodal involvement presented advanced disease stage and poor prognosis. 2. Oncogenic mutations were associated with multiple extranodal involvement. 3. Increased Treg‐recruiting activity and decreased extracellular matrix expression of the tumor microenvironment correlated with multiple extranodal involvement.