Saliva protein biomarkers to detect oral squamous cell carcinoma in a high-risk population in Taiwan

Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11549-11554. doi: 10.1073/pnas.1612368113. Epub 2016 Sep 23.


Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan's Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.

Keywords: biomarkers; early detection; oral cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Chromatography, Liquid
  • Demography
  • Early Detection of Cancer
  • Endoplasmic Reticulum Chaperone BiP
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / pathology
  • Neoplasm Staging
  • Risk Factors
  • Saliva / metabolism
  • Salivary Proteins and Peptides / metabolism*
  • Taiwan


  • Biomarkers, Tumor
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Salivary Proteins and Peptides