An Interpretable Four-Gene Cell-Cycle Signature Links Malignant Progression to Adverse Survival in Adult Primary...

Adult diffuse gliomas are biologically heterogeneous and clinically lethal. We evaluated whether a compact transcriptomic program could summarize malignant progression and adverse survival.

We analyzed adult primary WHO grades II-IV gliomas from the CGGA mRNAseq_693 cohort and used CGGA mRNAseq_325 as an independent validation cohort. CDK1, CCNB2, CDCA3, and PTTG1 were prioritized through a transparent, literature-informed mitotic-gene framework. Four classifiers were evaluated by five-fold cross-validation repeated 20 times, with all preprocessing restricted to each training fold. A training-defined four-gene score was assessed by Kaplan-Meier and Cox models.

The primary cohort contained 415 tumors, including 396 with evaluable survival. We identified 773 differentially expressed genes between WHO grade IV and WHO grades II/III tumors, and all four candidate genes increased monotonically with grade. In repeated cross-validation, the SVM achieved the highest mean AUROC of 0.793 ± 0.048 (95% CI 0.784-0.802), with average precision of 0.701 ± 0.063. In the independent CGGA mRNAseq_325 cohort (n = 226), logistic regression achieved an AUROC of 0.792. The four-gene score and a broader four-marker proliferation index showed similar discrimination, supporting the interpretation of the signature as a compact proliferation-axis proxy. The training-set median cut-off was -0.153. The score remained associated with shorter survival after adjustment for age, grade, and IDH status in the primary cohort (n = 359; HR = 1.28, 95% CI 1.10-1.49; p = 0.002) and in the independent cohort (n = 217; HR = 1.58, 95% CI 1.25-2.00; p < 0.001).

The four-gene score captures grade-associated proliferative biology and reproducible survival risk across two CGGA cohorts. It is a research biomarker rather than a standalone diagnostic or clinical decision tool.