Clinical Oral Investigations

, Volume 23, Issue 9, pp 3557–3563 | Cite as

Identification of salivary metabolites for oral squamous cell carcinoma and oral epithelial dysplasia screening from persistent suspicious oral mucosal lesions

  • Shigeo Ishikawa
  • David T. W. Wong
  • Masahiro SugimotoEmail author
  • Frederico Omar Gleber-Netto
  • Feng Li
  • Michael Tu
  • Yong Zhang
  • David Akin
  • Mitsuyoshi Iino
Original Article



To identify salivary metabolite biomarkers to differentiate patients with oral squamous cell carcinoma and oral epithelial dysplasia (OSCC/OED) from those with persistent suspicious oral mucosal lesions (PSOML).

Subjects and methods

Whole unstimulated saliva samples were collected from age-, sex-, and race-matched patients who had a lesion in the oral cavity and for whom open biopsies were performed. The patients included OSCC (n = 6), OED (n = 10), and PSOML (n = 32). Hydrophilic metabolites in saliva samples were comprehensively analyzed using capillary electrophoresis mass spectrometry. To evaluate the discrimination ability of a combination of multiple markers, a multiple logistic regression (MLR) model was developed to differentiate OSCC/OED from PSOML.


Six metabolites were significantly different in OSCC/OED compared with PSOML. From these six metabolites, ornithine, o-hydroxybenzoate, and ribose 5-phosphate (R5P) were used to develop the MLR model, which resulted in a high value for the area under receiver operating characteristic curve (AUC 0.871, 95% confidential interval (CI) 0.760–0.982; p < 0.001) to discriminate OSCC/OED from PSOML.


This is the first study to identify salivary metabolites that discriminate OSCC/OED from PSOML rather than from healthy controls. The profiles of salivary metabolites were significantly different between OSCC/OED and PSOML. The ability to discriminate OSCC/OED from PSOML is important for dentists who are not oral surgery specialists. These salivary metabolites showed potential for non-invasive screening to discriminate OSCC/OED from PSOML.

Clinical relevance

Salivary metabolites in this study showed potential for non-invasive screening to discriminate OSCC/OED from PSOML.


Metabolites Oral squamous cell carcinoma Oral epithelial dysplasia Screening Saliva 



We thank Edanz Group (, for editing a draft of this manuscript.


This work was supported by grants from Yamagata Prefecture, Tsuruoka, Japan, and the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) KAKENHI (16K11742 and 17K11897).

Compliance with ethical standards

Conflict of interest

David Wong is co-founder of RNAmeTRIX Inc., a molecular diagnostic company. He holds equity in RNAmeTRIX, and serves as a company Director and Scientific Advisor. The University of California also holds equity in RNAmeTRIX. Intellectual property that David Wong invented and which was patented by the University of California has been licensed to RNAmeTRIX. Dr. Wong is consultant to GlaxoSmithKlein, Wrigley, and Colgate-Palmolive. Masahiro Sugimoto is a co-founder of SalivaTech Co. LTD.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The Ethics Committee of University of California, Los Angeles, Faculty (School) of Dentistry, approved this study protocol.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

784_2018_2777_MOESM1_ESM.xlsx (19 kb)
ESM 1 (XLSX 18 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shigeo Ishikawa
    • 1
    • 2
  • David T. W. Wong
    • 2
  • Masahiro Sugimoto
    • 3
    Email author
  • Frederico Omar Gleber-Netto
    • 2
  • Feng Li
    • 2
  • Michael Tu
    • 2
  • Yong Zhang
    • 2
  • David Akin
    • 2
  • Mitsuyoshi Iino
    • 1
  1. 1.Department of Dentistry, Oral and Maxillofacial Plastic and Reconstructive Surgery, Faculty of MedicineYamagata UniversityYamagataJapan
  2. 2.School of DentistryUniversity of CaliforniaLos AngelesUSA
  3. 3.Health Promotion and Pre-emptive Medicine, Research and Development Center for Minimally Invasive TherapiesTokyo Medical UniversityTokyoJapan

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