ArticleTranslational oncology2026
Integrative bulk and single-cell transcriptomics identifies a HERC5-linked immune-attenuated risk program for pulmonary metastasis/relapse in osteosarcoma.
Article in Translational oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPulmonary metastasis/relapse (PM/R) is a major cause of osteosarcoma treatment failure. We aimed to develop a compact transcriptomic PM/R risk score and characterize associated immune and single-cell programs.
methodsTARGET-OS bulk RNA-seq was used for discovery and GSE21257 for external validation. Differential expression, multi-algorithm feature selection and LASSO regression were used to construct the score. Clinical associations were assessed by PM/R classification, survival and calibration analyses. Immune signature scoring, weighted gene co-expression network analysis (WGCNA), single-cell projection, in silico virtual HERC5 knockout, PROGENy/DoRothEA, CellChat and exploratory drug-reversal analyses were used for biological interpretation.
resultsA 9-gene score comprising HERC5, GPR141, SLC45A4, LCN15, MXI1, UCK2, KRTAP13-2, KCNK6 and TRABD2A showed high apparent discrimination in TARGET-OS (AUC = 0.922). A reduced seven-gene GSE21257 implementation achieved an AUC of 0.728. High-risk tumors were enriched for PM/R and had poorer event-free survival (HR = 3.14, 95% CI, 1.60-6.16) and overall survival (HR = 3.75, 95% CI, 1.60-8.79). High-risk disease showed reduced antigen-presentation, IFN-gamma, T-cell, CD8 T-cell, NK-cell and cytotoxicity signatures. WGCNA identified a protective immune module, while single-cell and in silico virtual-knockout analyses prioritized HERC5 as a candidate immune-associated node linked to antigen-presentation genes. Regulatory and communication analyses suggested reduced JAK-STAT/IRF activity and SPP1/MIF-centered microenvironmental signaling.
conclusionsThis study defines a PM/R-focused transcriptomic risk score and links high-risk osteosarcoma to immune attenuation and a HERC5-associated antigen-presentation program, providing a framework for future validation.
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