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

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

doi:10.1002/jha2.1046

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

EJHaem. 2024 Nov 14;5(6):1201-1214. doi: 10.1002/jha2.1046. eCollection 2024 Dec.

Authors

Keiichiro Hattori^{1

2}, Kenichi Makishima², Sakurako Suma², Yoshiaki Abe^{1

2}, Yasuhito Suehara², Tatsuhiro Sakamoto^{1

2}, Naoki Kurita^{1

2}, Ryota Ishii³, Ryota Matsuoka⁴, Masahide Matsuda⁵, Takao Tsurubuchi⁵, Ryo Nishikawa⁶, Shota Tanaka⁷, Akitake Mukasa⁸, Yoshitaka Narita⁹, Koichi Ichimura¹⁰, Motoo Nagane¹¹, Shingo Takano⁵, Bryan J Mathis¹², Eiichi Ishikawa⁵, Daisuke Matsubara⁴, Shigeru Chiba^{1

2}, Mamiko Sakata-Yanagimoto^{1

2

13}

Affiliations

¹ Department of Hematology Institute of Medicine University of Tsukuba Tsukuba Japan.
² Department of Hematology University of Tsukuba Hospital Tsukuba Japan.
³ Department of Biostatistics Institute of Medicine University of Tsukuba Tsukuba Japan.
⁴ Department of Pathology Institute of Medicine University of Tsukuba Tsukuba Japan.
⁵ Department of Neurosurgery Institute of Clinical Medicine University of Tsukuba Tsukuba Japan.
⁶ Department of Neuro-Oncology/Neurosurgery Saitama Medical University International Medical Center Saitama Japan.
⁷ Department of Neurosurgery Graduate School of Medicine The University of Tokyo Tokyo Japan.
⁸ Department of Neurosurgery Graduate School of Medical Sciences Kumamoto University Kumamoto Japan.
⁹ Department of Neurosurgery and Neuro-Oncology National Cancer Center Hospital Tokyo Japan.
¹⁰ Department of Brain Disease Translational Research Juntendo University Graduate School of Medicine Tokyo Japan.
¹¹ Department of Neurosurgery Kyorin University Faculty of Medicine Tokyo Japan.
¹² Department of Cardiovascular Surgery Institute of Medicine University of Tsukuba Tsukuba Japan.
¹³ Division of Advanced Hemato-Oncology Transborder Medical Research Center University of Tsukuba Tsukuba Japan.

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.

Keywords: Gliosis; Primary central nervous system lymphoma; Tumor microenvironment in central nervous system.