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TMEM106A as a Macrophage-Associated Biomarker of Prognosis in IDH-Wildtype Glioma: Integrative Multi-Omics and
Wen-Shin Song1,2, Pei-Chi Chang3, Dueng-Yuan Hueng2
1Division of Neurosurgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan.
Introduction:
Gliomas remain aggressive despite current therapies, highlighting the urgent need for new biomarkers and targets. Transmembrane protein 106A (TMEM106A), implicated as a tumor suppressor in various cancers, has an unclear role in gliomas. We hypothesized that TMEM106A expression associates with tumor aggressiveness and may serve as a prognostic, microenvironmental biomarker.
Methods:
We integrated TCGA and CGGA bulk RNA-seq, single-cell (GSE131928, GSE89567), spatial (Ivy Atlas, Visium), and immunohistochemistry (n = 79) to evaluate TMEM106A. Differential expression used limma. Survival used Kaplan-Meier and multivariable Cox models. Immune contexture used a 12-cell-state deconvolution and CIBERSORT. GSEA assessed hallmark pathways. Drug sensitivity was inferred using pRRophetic. Immunotherapy modeling combined TCGA expression with TCIA immunophenoscore and PD-L1.
Results:
(1) TMEM106A mRNA is significantly upregulated in high-grade gliomas compared to lower-grade gliomas and normal brain. (2) In IDH-wildtype tumors, differential analyses highlight roles of TMEM106A and TMEM106C; high expression links to poorer prognosis. (3) TMEM106A is an independent prognostic factor associated with aggressive behavior, especially in IDH-wildtype astrocytomas. (4) Upregulation is confirmed by immunohistochemistry. (5) High TMEM106A associates with pro-inflammatory signatures and higher inferred fractions of myeloid cells and granulocytes. (6) Single-cell RNA-seq shows enrichment in myeloid lineages, and (7) CIBERSORT shows modest positive correlations with polarized macrophage signatures. (8) Spatial transcriptomics shows higher TMEM106A in myeloid-rich regions, consistent with a microenvironmental readout. (9) In IDH-wildtype tumors, pRRophetic predicts lower IC50 for multiple targeted agents in TMEM106A-high tumors. (10) TMEM106A-high IDH-wildtype tumors show higher IPS only when PD-1 is "on," suggesting a context-dependent, inflamed-but-suppressed state.
Conclusion:
TMEM106A independently predicts survival and correlates with myeloid-enriched transcriptional states in gliomas. Given its high expression in myeloid lineages in single-cell data, bulk upregulation is potentially driven by myeloid infiltration rather than tumor-cell intrinsic mechanisms. All findings are correlative; prospective studies are needed before any clinical use is considered.
