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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

Abstract

Objective

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.

Results

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.

Conclusions

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.

Keywords

Metabolites Oral squamous cell carcinoma Oral epithelial dysplasia Screening Saliva 

Notes

Acknowledgments

We thank Edanz Group (www.edanzediting.com/ac), for editing a draft of this manuscript.

Funding

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)

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386CrossRefGoogle Scholar
  2. 2.
    Malik UU, Zarina S, Pennington SR (2016) Oral squamous cell carcinoma: key clinical questions, biomarker discovery, and the role of proteomics. Arch Oral Biol 63:53–65CrossRefGoogle Scholar
  3. 3.
    Massano J, Regateiro FS, Januario G, Ferreira A (2006) Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102(1):67–76CrossRefGoogle Scholar
  4. 4.
    Balasundaram I, Payne KF, Al-Hadad I, Alibhai M, Thomas S, Bhandari R (2014) Is there any benefit in surgery for potentially malignant disorders of the oral cavity? J Oral Pathol Med 43(4):239–244CrossRefGoogle Scholar
  5. 5.
    Arduino PG, Surace A, Carbone M, Elia A, Massolini G, Gandolfo S, Broccoletti R (2009) Outcome of oral dysplasia: a retrospective hospital-based study of 207 patients with a long follow-up. J Oral Pathol Med 38(6):540–544CrossRefGoogle Scholar
  6. 6.
    Silverman S Jr, Gorsky M, Lozada F (1984) Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer 53(3):563–568CrossRefGoogle Scholar
  7. 7.
    Schepman KP, van der Meij EH, Smeele LE, van der Waal I (1998) Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from the Netherlands. Oral Oncol 34(4):270–275CrossRefGoogle Scholar
  8. 8.
    Lind PO (1987) Malignant transformation in oral leukoplakia. Scand J Dent Res 95(6):449–455Google Scholar
  9. 9.
    Rashid A, Warnakulasuriya S (2015) The use of light-based (optical) detection systems as adjuncts in the detection of oral cancer and oral potentially malignant disorders: a systematic review. J Oral Pathol Med 44(5):307–328CrossRefGoogle Scholar
  10. 10.
    Macey R, Walsh T, Brocklehurst P, Kerr AR, Liu JLY, Lingen MW, Ogden GR, Warnakulasuriya S, Scully C (2015) Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions. Cochrane Database Syst Rev.  https://doi.org/10.1002/14651858.CD010276.pub2
  11. 11.
    Rethman MP, Carpenter W, Cohen EE, Epstein J, Evans CA, Flaitz CM, Graham FJ, Hujoel PP, Kalmar JR, Koch WM, Lambert PM, Lingen MW, Oettmeier BW Jr, Patton LL, Perkins D, Reid BC, Sciubba JJ, Tomar SL, Wyatt AD Jr, Aravamudhan K, Frantsve-Hawley J, Cleveland JL, Meyer DM, American Dental C (2010) Association council on scientific affairs expert panel on screening for oral squamous cell, evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas. J Am Dent Assoc 141(5):509–520CrossRefGoogle Scholar
  12. 12.
    Petruzzi M, Lucchese A, Baldoni E, Grassi FR, Serpico R (2010) Use of Lugol’s iodine in oral cancer diagnosis: an overview. Oral Oncol 46(11):811–813CrossRefGoogle Scholar
  13. 13.
    Metgud R, Patel S (2014) Serum and salivary levels of albumin as diagnostic tools for oral pre-malignancy and oral malignancy. Biotech Histochem 89(1):8–13CrossRefGoogle Scholar
  14. 14.
    Punyani SR, Sathawane RS (2013) Salivary level of interleukin-8 in oral precancer and oral squamous cell carcinoma. Clin Oral Investig 17(2):517–524CrossRefGoogle Scholar
  15. 15.
    Wei J, Xie G, Zhou Z, Shi P, Qiu Y, Zheng X, Chen T, Su M, Zhao A, Jia W (2011) Salivary metabolite signatures of oral cancer and leukoplakia. Int J Cancer 129(9):2207–2217CrossRefGoogle Scholar
  16. 16.
    Ishikawa S, Sugimoto M, Kitabatake K, Sugano A, Nakamura M, Kaneko M, Ota S, Hiwatari K, Enomoto A, Soga T, Tomita M, Iino M (2016) Identification of salivary metabolomic biomarkers for oral cancer screening. Sci Rep 6:31520CrossRefGoogle Scholar
  17. 17.
    Henson BS, Wong DT (2010) Collection, storage, and processing of saliva samples for downstream molecular applications. Methods Mol Biol 666:21–30CrossRefGoogle Scholar
  18. 18.
    Ishikawa S, Sugimoto M, Kitabatake K, Tu M, Sugano A, Yamamori I, Iba A, Yusa K, Kaneko M, Ota S, Hiwatari K, Enomoto A, Masaru T, Iino M (2017) Effect of timing of collection of salivary metabolomic biomarkers on oral cancer detection. Amino Acids 49(4):761–770CrossRefGoogle Scholar
  19. 19.
    Sugimoto M, Wong DT, Hirayama A, Soga T, Tomita M (2010) Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics 6(1):78–95CrossRefGoogle Scholar
  20. 20.
    Saeed AI, Bhagabati NK, Braisted JC, Liang W, Sharov V, Howe EA, Li J, Thiagarajan M, White JA, Quackenbush J (2006) TM4 microarray software suite. Methods Enzymol 411:134–193CrossRefGoogle Scholar
  21. 21.
    Caso G, McNurlan MA, McMillan ND, Eremin O, Garlick PJ (2004) Tumour cell growth in culture: dependence on arginine. Clin Sci 107(4):371–379CrossRefGoogle Scholar
  22. 22.
    Cynober L (1994) Can arginine and ornithine support gut functions? Gut 35(1 Suppl):S42–S45CrossRefGoogle Scholar
  23. 23.
    Liu R, Li Q, Ma R, Lin X, Xu H, Bi K (2013) Determination of polyamine metabolome in plasma and urine by ultrahigh performance liquid chromatography-tandem mass spectrometry method: application to identify potential markers for human hepatic cancer. Anal Chim Acta 791:36–45CrossRefGoogle Scholar
  24. 24.
    Giskeodegard GF, Bertilsson H, Selnaes KM, Wright AJ, Bathen TF, Viset T, Halgunset J, Angelsen A, Gribbestad IS, Tessem MB (2013) Spermine and citrate as metabolic biomarkers for assessing prostate cancer aggressiveness. PLoS One 8(4):e62375CrossRefGoogle Scholar
  25. 25.
    Takayama T, Tsutsui H, Shimizu I, Toyama T, Yoshimoto N, Endo Y, Inoue K, Todoroki K, Min JZ, Mizuno H, Toyo’Oka T (2016) Diagnostic approach to breast cancer patients based on target metabolomics in saliva by liquid chromatography with tandem mass spectrometry. Clin Chim Acta 452:18–26CrossRefGoogle Scholar
  26. 26.
    Levin VA, Uhm JH, Jaeckle KA, Choucair A, Flynn PJ, Yung WKA, Prados MD, Bruner JM, Chang SM, Kyritsis AP, Gleason MJ, Hess KR (2000) Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. Clin Cancer Res 6(10):3878–3884Google Scholar
  27. 27.
    Jung YS, Najy AJ, Huang W, Sethi S, Snyder M, Sakr W, Dyson G, Huttemann M, Lee I, Ali-Fehmi R, Franceschi S, Struijk L, Kim HE, Kato I, Kim HC (2017) HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer. Oncotarget 8(31):51530–51541CrossRefGoogle Scholar
  28. 28.
    Sethi S, Ali-Fehmi R, Franceschi S, Struijk L, van Doorn LJ, Quint W, Albashiti B, Ibrahim M, Kato I (2012) Characteristics and survival of head and neck cancer by HPV status: a cancer registry-based study. Int J Cancer 131(5):1179–1186CrossRefGoogle Scholar
  29. 29.
    Mellin H, Friesland S, Lewensohn R, Dalianis T, Munck-Wikland E (2000) Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer 89(3):300–304CrossRefGoogle Scholar
  30. 30.
    Sedaghat AR, Zhang Z, Begum S, Palermo R, Best S, Ulmer KM, Levine M, Zinreich E, Messing BP, Gold D, Wu AA, Niparko KJ, Kowalski J, Hirata RM, Saunders JR, Westra WH, Pai SI (2009) Prognostic significance of human papillomavirus in oropharyngeal squamous cell carcinomas. Laryngoscope 119(8):1542–1549CrossRefGoogle Scholar
  31. 31.
    Polz-Dacewicz M, Strycharz-Dudziak M, Dworzanski J, Stec A, Kocot J (2016) Salivary and serum IL-10, TNF-alpha, TGF-beta, VEGF levels in oropharyngeal squamous cell carcinoma and correlation with HPV and EBV infections. Infect Agent Cancer 11:45CrossRefGoogle Scholar
  32. 32.
    Wan Y, Vagenas D, Salazar C, Kenny L, Perry C, Calvopina D, Punyadeera C (2017) Salivary miRNA panel to detect HPV-positive and HPV-negative head and neck cancer patients. Oncotarget 8(59):99990–100001CrossRefGoogle Scholar
  33. 33.
    Tang KD, Kenny L, Perry C, Frazer I, Punyadeera C (2017) The overexpression of salivary cytokeratins as potential diagnostic biomarkers in head and neck squamous cell carcinomas. Oncotarget 8(42):72272–72280CrossRefGoogle Scholar
  34. 34.
    Wang Q, Gao P, Wang X, Duan Y (2014) Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma. Clin Chim Acta 427:79–85CrossRefGoogle Scholar

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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