ArticleFrontiers in immunology2026
Plasma HERV-K envelopE RNA: a minimally invasive biomarker for lung adenocarcinoma detection and prognostic assessment in the context of conventional serum tumor markers.
Article in Frontiers in immunology, 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
Introduction: Early detection of lung adenocarcinoma (LUAD) remains challenging because low-dose computed tomography produces many false-positive pulmonary nodules and conventional serum tumor markers show histology-dependent diagnostic performance. We investigated whether plasma HERV-K env mRNA could serve as a minimally invasive biomarker for subtype-specific diagnosis and prognostic assessment in lung cancer. Methods: This retrospective single-center study enrolled 379 subjects, including 249 patients with non-small cell lung cancer (162 LUAD and 87 lung squamous cell carcinoma [LUSC]), 30 patients with malignant pulmonary nodules, 50 patients with benign pulmonary nodules, and 50 healthy controls. HERV-K env mRNA was quantified in tumor tissues, paired adjacent tissues, and EDTA-anticoagulated plasma by qRT-PCR. Associations with clinicopathological variables, tissue-plasma concordance, correlations with conventional serum tumor markers, ROC diagnostic performance, Kaplan-Meier survival, and multivariable Cox regression were analyzed. Results: HERV-K env mRNA was significantly upregulated in NSCLC tissues versus paired adjacent tissues (P < 0.0001) and was higher in LUAD than in LUSC (P < 0.0001). Tissue expression increased with advanced T stage, lymph node metastasis, and higher TNM stage (all P < 0.0001). Plasma HERV-K env mRNA levels were significantly elevated in lung cancer compared with benign pulmonary nodules and healthy controls (P < 0.0001) and correlated strongly with tissue expression in both LUSC (r = 0.9025) and LUAD (r = 0.7305). ROC analysis showed excellent performance for stage I/II LUAD versus healthy controls (AUC = 0.914), moderate performance for malignant pulmonary nodules versus healthy controls (AUC = 0.758), but limited performance for early-stage LUSC (AUC = 0.505). Plasma HERV-K env mRNA showed no significant correlations with conventional serum tumor markers. High plasma HERV-K env mRNA was associated with poorer overall survival in LUAD (P = 0.035), and multivariable Cox regression supported independent prognostic value in the overall cohort. Discussion: Plasma HERV-K env mRNA captures a biologically plausible and analytically non-redundant signal with the strongest current clinical promise in LUAD rather than LUSC. Its LUAD performance appears competitive with published single-marker serum assays, but broader clinical application and comparison with optimized conventional multi-marker panels require prospective multicenter and same-cohort validation.
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