A signature of saliva-derived exosomal small RNAs as predicting biomarker for esophageal carcinoma: a multicenter prospective study

Mol Cancer. 2022 Jan 18;21(1):21. doi: 10.1186/s12943-022-01499-8.


Background: The tRNA-derived small RNAs (tsRNAs) are produced in a nuclease-dependent manner in responses to variety of stresses that are common in cancers. We focus on a cancer-enriched tsRNA signature to develop a salivary exosome-based non-invasive biomarker for human esophageal squamous cell carcinoma (ESCC).

Methods: Cancer-enriched small RNAs were identified by RNA sequencing of salivary exosomes obtained from ESCC patients (n = 3) and healthy controls (n = 3) in a pilot study and further validated in discovery cohort (n = 66). A multicenter prospective observational study was conducted in two ESCC high-incidence regions (n = 320 and 200, respectively) using the newly developed biomarker signature.

Results: The tsRNA (tRNA-GlyGCC-5) and a previously undocumented small RNA were specifically enriched in salivary exosomes of ESCC patients, ESCC tissues and ESCC cells. The bi-signature composed of these small RNAs was able to discriminate ESCC patients from the controls with high sensitivity (90.50%) and specificity (94.20%). Based on the bi-signature Risk Score for Prognosis (RSP), patients with high-RSP have both shorter overall survival (OS) (HR 4.95, 95%CI 2.90-8.46) and progression-free survival (PFS) (HR 3.69, 95%CI 2.24-6.10) than those with low-RSP. In addition, adjuvant therapy improved OS (HR 0.47, 95%CI 0.29-0.77) and PFS (HR 0.36, 95%CI 0.21-0.62) only for patients with high but not low RSP. These findings are consistent in both training and validation cohort.

Conclusions: The tsRNA-based signature not only has the potential for diagnosis and prognosis but also may serve as a pre-operative biomarker to select patients who would benefit from adjuvant therapy.

Trial registration: A prospective study of diagnosis biomarkers of esophageal squamous cell carcinoma, ChiCTR2000031507 . Registered 3 April 2016 - Retrospectively registered.

Keywords: Esophageal carcinoma; Liquid-biopsy signature; Pre-operative biomarker of adjuvant therapy; Sequencing of salivary extracellular vesicles; Transfer RNA-derived small RNA; tRNA-derived fragments.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor*
  • Combined Modality Therapy
  • Disease Management
  • Esophageal Neoplasms / diagnosis*
  • Esophageal Neoplasms / etiology
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / therapy
  • Exosomes / metabolism*
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • Neoplasm Grading
  • Neoplasm Staging
  • Prognosis
  • Prospective Studies
  • RNA, Small Untranslated / genetics*
  • RNA, Small Untranslated / metabolism
  • Saliva / metabolism*
  • Sensitivity and Specificity


  • Biomarkers, Tumor
  • RNA, Small Untranslated

Associated data

  • ChiCTR/ChiCTR2000031507