Development and Validation of Salivary Exosomal Tri-RNA Liquid Biopsy in Esophageal Carcinoma: A Multicenter Study
Xiaona Lin, Jiakang Ma, Kai Li, Mengyuan Hu, Yinhui Jiang, Junkuo Li, Yi Guo, Dianzheng Zhang, Hongzheng Ren, Xiaofu Qiu, Songwang Cai, Shuyao Zhang, Shegan Gao, Hao ZhangPURPOSE
Exosomal RNAs are emerging as cancer signatures, and saliva is a noninvasive biospecimen. Given the high mortality of patients with esophageal squamous cell carcinoma (ESCC) and limited early detection tools, we investigated a salivary exosome‑based Tri-signature for its diagnostic and prognostic potential.
MATERIALS AND METHODS
The salivary exosome‑based signature (ie, a chimeric RNA seG-NchiRNA, a tRNA fragment GlyGCC-5, and a novel sRESE RNA) was quantified by qRT-PCR in a multicenter observational study across two ESCC-endemic regions. Model development and validation were performed in the training (n = 359) and validation (n = 225) cohorts using logistic regression, survival analyses, and Shapley Additive exPlanations–based feature interpretation.
RESULTS
The Tri-signature showed excellent diagnostic accuracy (training cohort: AUC, 0.987; validation cohort: AUC, 0.964) and robust prognostic value (training cohort: overall survival [OS] hazard ratio [HR], 5.52, progression-free survival [PFS] HR, 4.46; validation cohort: OS HR, 4.76, PFS HR, 2.79). In the high Combined Risk Score for Prognosis (CRSP) subgroup, patients with relatively lower CRSP derived significant benefit from adjuvant therapy (training cohort: OS HR, 0.54, PFS HR, 0.47; validation cohort: OS HR, 0.38, PFS HR = 0.32), whereas no such benefit was observed in low Tri-signature patients. The Tri-signature exhibited strong early diagnostic performance, distinguishing early-stage ESCC without lymph node metastasis from healthy controls (training cohort: AUC = 0.975; validation cohort: AUC = 0.950). Patients with early-stage ESCC and high CRSP had significantly worse outcomes (training cohort: OS HR, 5.09, RFS HR, 3.80; validation cohort: OS HR, 8.79, RFS HR, 4.55).
CONCLUSION
The salivary exosome-based tri-RNA signature showed robust multicenter reproducibility and strong diagnostic, prognostic, and treatment response-predictive performance, supporting its translational potential as a noninvasive biomarker panel for ESCC management.