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Integrated Genomic and Tumor Microenvironment Subtyping Improved Risk Stratification in Primary Central Nervous System Lymphoma.

Xianggui Yuan·Qian Luo·Yurong Huang·Chaoyi Li·Teng Yu·Shanshan Guo·Qunyi Guo·Xueli Jin·Jiefeng Tong·Aiqi Zhao·Wen Lei·Xian Li·Baizhou Li·Shumei Wei·Wenbin Qian·Yun Liang
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Abstract

Current prognostic models fail to capture the biological complexity of primary central nervous system lymphoma (PCNSL). We integrated whole-genome sequencing and multiplex immunofluorescence in 68 treatment-na&#xef;ve patients to define four genomic subtypes (C1, C2, C3, and C4) with divergent survival (C4 worst: median overall survival [OS], 26&#x2009;months). In parallel, a novel tumor microenvironment (TME) classification based on CD8+T/M2 macrophage ratio stratified patients into High (>&#x2009;1.5), Intermediate (0.8-1.5), and Low (<&#x2009;0.8) groups. Unexpectedly, the Intermediate TME group showed the poorest outcomes (5-year OS: 10%). Integration revealed a lethal subgroup (C4&#x2009;+&#x2009;Intermediate TME; 9.8% of cohort) with a median OS of 3.0&#x2009;months (hazard ratio&#x2009;=&#x2009;7.24, p&#x2009;=&#x2009;0.006). Prognostic nomograms incorporating these subtypes showed promising discriminative performance in internal validation (C-index >&#x2009;0.78), but external validation is needed. Together, these findings identify a high-risk biological subset and provide a hypothesis-generating framework for future biomarker-driven risk stratification and therapeutic discovery in PCNSL.

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HumansTumor MicroenvironmentCentral Nervous System NeoplasmsFemaleMalePrognosisMiddle AgedAgedLymphomaGenomicsAdultRisk AssessmentWhole Genome SequencingCD8+T/M2 ratiogenomic subtypesprimary central nervous system lymphomaprognostic stratificationtumor microenvironmentJournal Article

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Xianggui Yuan, Qian Luo, Yurong Huang, Chaoyi Li, Teng Yu, Shanshan Guo, Qunyi Guo, Xueli Jin, Jiefeng Tong, Aiqi Zhao, Wen Lei, Xian Li, Baizhou Li, Shumei Wei, Wenbin Qian, Yun Liang. 2026-06-07. Integrated Genomic and Tumor Microenvironment Subtyping Improved Risk Stratification in Primary Central Nervous System Lymphoma.. https://doi.org/10.1002/ajh.70396

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