Journal of neuroimmunology · 2026
Reassessment of a four-gene NK-cell-lineage-associated prognostic score in histologically defined grade 3 glioma.
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Li Jiye, Wu Mingxing, Xiong Xian, Zhou Tingting, Di Fei
Аннотация
BACKGROUND: Historical anaplastic glioma comprises molecularly heterogeneous tumors. We reassessed a four-gene score derived from an NK-cell-lineage-associated panel, focusing on selection stability, standardized validation, and incremental value beyond established molecular features.
METHODS: We analyzed histologically recorded grade III gliomas with overall survival longer than 60 days from TCGA (training; n = 248), GSE16011 (n = 80), and REMBRANDT/GSE108474 (n = 67). Of 76 historical candidates, 73 mapped to current TCGA expression data. Ten-fold cross-validated LASSO Cox regression and 100 bootstrap resamples assessed stability. The submitted four-gene score (ARL4C, ERBB2, IQGAP1, and SMAD7) was refitted in TCGA. The continuous score was primary, and one TCGA-derived cutoff was applied unchanged to validation cohorts. TCGA models adjusted for age, sex, histology, and integrated IDH/1p19q subtype.
RESULTS: The score was associated with survival in TCGA (HR per SD, 2.37; 95% CI, 1.91-2.93) and GSE16011 (HR, 1.84; 95% CI, 1.43-2.36), but not REMBRANDT (HR, 0.93; 95% CI, 0.70-1.23; P = 0.601); validation-cohort heterogeneity was significant (P = 0.00046). In 245 TCGA patients with molecular data, the adjusted HR was 1.95 (95% CI, 1.37-2.76). Adding the score increased Harrell's C from 0.810 to 0.833 and reduced AIC from 676.23 to 664.31. At lambda.1se, only ARL4C and ERBB2 among the four genes were retained; bootstrap frequencies ranged from 0.25 to 0.74.
CONCLUSIONS: The score retained an adjusted association in TCGA and replicated in GSE16011, but failed in REMBRANDT and showed incomplete gene-selection stability. No protein-level, single-cell, or spatial validation was performed.It should be considered an exploratory bulk-transcriptomic score, not a validated NK-cell-specific biomarker or a clinically validated decision tool. Prospective molecularly classified cohorts, locked cross-platform preprocessing, protein-level validation, and cell-resolved studies are required.
METHODS: We analyzed histologically recorded grade III gliomas with overall survival longer than 60 days from TCGA (training; n = 248), GSE16011 (n = 80), and REMBRANDT/GSE108474 (n = 67). Of 76 historical candidates, 73 mapped to current TCGA expression data. Ten-fold cross-validated LASSO Cox regression and 100 bootstrap resamples assessed stability. The submitted four-gene score (ARL4C, ERBB2, IQGAP1, and SMAD7) was refitted in TCGA. The continuous score was primary, and one TCGA-derived cutoff was applied unchanged to validation cohorts. TCGA models adjusted for age, sex, histology, and integrated IDH/1p19q subtype.
RESULTS: The score was associated with survival in TCGA (HR per SD, 2.37; 95% CI, 1.91-2.93) and GSE16011 (HR, 1.84; 95% CI, 1.43-2.36), but not REMBRANDT (HR, 0.93; 95% CI, 0.70-1.23; P = 0.601); validation-cohort heterogeneity was significant (P = 0.00046). In 245 TCGA patients with molecular data, the adjusted HR was 1.95 (95% CI, 1.37-2.76). Adding the score increased Harrell's C from 0.810 to 0.833 and reduced AIC from 676.23 to 664.31. At lambda.1se, only ARL4C and ERBB2 among the four genes were retained; bootstrap frequencies ranged from 0.25 to 0.74.
CONCLUSIONS: The score retained an adjusted association in TCGA and replicated in GSE16011, but failed in REMBRANDT and showed incomplete gene-selection stability. No protein-level, single-cell, or spatial validation was performed.It should be considered an exploratory bulk-transcriptomic score, not a validated NK-cell-specific biomarker or a clinically validated decision tool. Prospective molecularly classified cohorts, locked cross-platform preprocessing, protein-level validation, and cell-resolved studies are required.