Comprehensive circRNA profiling of platelets and exosomes identifies hsa_circ_0061274 as a novel biomarker for lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is usually detected late; sensitive, minimally invasive early-detection tools are urgently needed. Circular RNAs (circRNAs) in liquid biopsies are promising cancer biomarkers, yet it remains unclear which blood component-platelets or plasma exosomes-offers the richest and most informative circRNA source. Materials and methods: High-throughput RNA sequencing was performed on platelets and plasma exosomes collected from LUAD patients and age-matched healthy donors. Differential circRNAs expression was analyzed after stringent quality filtering and normalization. A candidate reference gene was selected by stability testing (geNorm, NormFinder); diagnostic performance of the top LUAD-associated circRNA was validated in independent cohorts encompassing healthy controls and patients with benign pulmonary nodules; ROC curves were generated and AUCs calculated. Results: Platelets contained 15-20-fold more distinct circRNAs than plasma exosomes. hsa_circ_0001380 was identified as a stably expressed reference suitable for platelet circRNA quantification. hsa_circ_0061274 was significantly down-regulated in LUAD platelets (log2FC ≈ -1.8, FDR < 0.01). In validation cohorts, hsa_circ_0061274 discriminated LUAD from healthy controls with an AUC of 0.85 (95% CI 0.79-0.91), from benign pulmonary nodules with an AUC of 0.75 (95% CI 0.68-0.82), and stage I LUAD with an Area Under the Curve (AUC) of 0.68 (95% CI 0.60-0.76). Platelet-derived circRNAs thus provide robust, minimally invasive biomarkers for early LUAD detection and pulmonary nodule characterization.