Abstract
Lung cancer diagnosis still relies on imaging and tissue sampling, which can be invasive and costly. Moreover, anatomic staging alone does not fully capture biological heterogeneity. Therefore, minimally invasive blood biomarkers are needed to support diagnosis and risk stratification. We integrated public transcriptomic data analyses with an independent serum-based enzyme-linked immunosorbent assay (ELISA) validation cohort. Using the Gene Expression Omnibus (GEO) dataset GSE40275, we compared RNA expression of tyrosine 3‑monooxygenase/tryptophan 5‑monooxygenase activation protein β (14‑3‑3β, encoded by the YWHAB gene) between 43 healthy control subjects and patients with distinct lung cancer pathological subtypes, including 11 cases of lung adenocarcinoma (LUAD) and 5 cases of lung squamous cell carcinoma (LUSC).Two additional GEO datasets, GSE29013 (30 LUAD and 25 LUSC patients) and GSE43580 (77 LUAD and 73 LUSC patients), were utilized to validate the differential 14-3-3β RNA expression between LUAD and LUSC subtypes. In the GSE29013 cohort, subgroup analyses were performed stratified by tumor stage, disease progression status, and clinical outcomes; Kaplan-Meier Plotter was applied to assess the associations of 14-3-3β expression with overall survival (OS) and post-progression survival (PPS). For serum-level validation, peripheral blood samples from 15 LUAD patients, 21 LUSC patients, and 32 healthy controls were examined via ELISA, with receiver operating characteristic curve analysis conducted to evaluate its diagnostic performance via calculation of the area under the curve (AUC). 14-3-3β RNA expression was higher in LUAD and LUSC than in controls (both p < 0.0001) and higher in LUSC than in LUAD (P = 0.005), which was confirmed in GSE29013 (P = 0.0140) and GSE43580 (P = 0.0222). In GSE29013, higher 14-3-3β expression was associated with tumor progression (P = 0.0440) and death (P = 0.0091), and predicted shorter OS (HR = 1.21; P = 0.0043) and PPS (HR = 1.55; P = 9.7e-05). Serum 14-3-3β levels were increased in LUAD and LUSC, yielding an AUC of 0.93 with 80.6% sensitivity and 100% specificity at a cutoff of 43.04 ng/mL. Across tissue transcriptomes and serum validation, 14-3-3β is associated with lung cancer presence, histological subtype, and survival outcomes, supporting its potential as a minimally invasive adjunct biomarker for diagnosis and prognostic assessment.