Plasma HERV-K envelopE RNA: a minimally invasive biomarker for lung adenocarcinoma detection and prognostic assessment in the context of conventional serum tumor markers.

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.