Association between microenvironment-related genes and prognosis of primary central nervous system lymphoma

EJHaem Pub Date : 2024-11-14 DOI:10.1002/jha2.1046

Keiichiro Hattori, Kenichi Makishima, Sakurako Suma, Yoshiaki Abe, Yasuhito Suehara, Tatsuhiro Sakamoto, Naoki Kurita, Ryota Ishii, Ryota Matsuoka, Masahide Matsuda, Takao Tsurubuchi, Ryo Nishikawa, Shota Tanaka, Akitake Mukasa, Yoshitaka Narita, Koichi Ichimura, Motoo Nagane, Shingo Takano, Bryan J. Mathis, Eiichi Ishikawa, Daisuke Matsubara, Shigeru Chiba, Mamiko Sakata-Yanagimoto

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Abstract

Background

Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients.

Methods

We analyzed expression levels of 770 neuroinflammation-related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the “recurrence group (RG)” or “non-recurrence group (NRG)” were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (n = 30).

Results

Forty-five of 770 NFR genes were highly expressed in the RG (3-year overall survival (OS, 22.2%), compared with the NRG group (3-year OS 66.7%). Signatures related to glial cells were enriched in the RG-associated gene set. Multivariate analysis revealed that high expressions of TUBB4A (p = 0.028, HR: 3.88), S100B (p = 0.046, HR: 3.093), and SLC6A1 (p = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells.

Conclusion

These data suggest that TME-related genes play a crucial role in the pathogenesis of PCNSL, complementing the well-known involvement of the NF-kB signaling pathway. TME targeting, especially glial cell-specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.

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微环境相关基因与原发性中枢神经系统淋巴瘤预后的关系

背景：原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见的淋巴系统恶性肿瘤。PCNSL肿瘤微环境（TME）的系统分析以前是通过基因表达分析进行的。我们研究了TME对PCNSL患者生存的预后影响，以建立新的预后生物标志物。方法：通过NanoString nCounter技术分析了30例PCNSL患者肿瘤样本中770个神经炎症相关（NFR）基因的表达水平。通过独立PCNSL队列（n = 30）的全转录组分析，鉴定并验证了与“复发组（RG）”或“非复发组（NRG）”相关的基因。结果：770个NFR基因中有45个在RG组中高表达（3年总生存率为22.2%），而NRG组的3年总生存率为66.7%。rg相关基因集中富集了与胶质细胞相关的特征。多因素分析显示，TUBB4A （p = 0.028, HR: 3.88）、S100B （p = 0.046, HR: 3.093）、SLC6A1 （p = 0.034, HR: 3.765）的高表达与死亡显著相关。在验证队列中，这三个基因的表达水平也与不良OS显著相关。免疫组化对TUBB4A、S100B和胶质细胞特异性蛋白（GFAP、OLIG2和CD68）的免疫组化染色显示RG胶质细胞中明显较高的阳性。结论：这些数据表明，tme相关基因在PCNSL的发病机制中起着至关重要的作用，补充了众所周知的NF-kB信号通路的参与。因此，TME靶向，特别是胶质细胞特异性蛋白，可能为PCNSL的所有阶段开辟新的和互补的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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EJHaem

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