TMEM164 mRNA in Adult Glioblastoma: Multicohort Overexpression and RIPK1 Co-Expression Without Prognostic Replication

Background/Objectives: Experimental work has implicated TMEM164 in glioblastoma radioresistance through post-translational inhibition of FASN and suppression of radiation-induced necroptosis, supported clinically by a dichotomised single-database survival analysis. We tested whether the previously reported transcript-level clinical association of TMEM164 is reproducible across independent human glioblastoma cohorts and characterised its relationship with tumour status, necroptosis-related transcripts and recurrence. Methods: Secondary analysis of four public resources: TCGA (n = 153), CGGA-693 (n = 104), CGGA-325 (n = 73), and 104 matched primary-recurrence pairs from GLASS. Overall survival was modelled by continuous Cox regression, pooled by Hartung–Knapp random-effects meta-analysis. Results:TMEM164 occupied a higher within-sample percentile in tumour than in non-tumour brains in all three cohorts (Cliff’s δ 0.68–0.85; all p ≤ 1.3 × 10−3), was co-expressed with RIPK1 (ρ 0.25–0.44; all q < 0.05), ranking 43rd of 19,985 genes, and was unchanged by adjustment for tumour composition. No association with overall survival replicated across cohorts, in the pooled analysis (HR 1.11, 95% CI 0.77–1.61; I2 = 49.9%), among irradiated patients or in confirmed IDH-wildtype cases; isolated nominally significant positive estimates arose in exploratory strata and were not reproduced elsewhere. With 277 events, the pooled interval excludes hazard ratios above approximately 1.6 per standard deviation, while smaller effects remain compatible. An optimal cutpoint generated HR 1.83 (p = 0.004) that did not survive correction for selection. TMEM164 protein was quantified in 0 of 99 CPTAC glioblastomas. Conclusions: Baseline bulk-tumour TMEM164 mRNA carries no reproducible prognostic information in adult glioblastoma. The proposed mechanism is post-translational and must be tested at the protein and activity level, on treatment-related tissue sampling.