A Review of Salivary Biomarker: A Tool for Early Oral Cancer Diagnosis



Department of Oral Pathology, Government Dental College and Hospital, Jaipur, India


The oral squamous cell carcinoma (OSCC) is one of the most common epithelial malignancies with significant morbidity and mortality. Recent observations indicate that the clinical and histological appearance of oral mucosa may not truly depict the damage occurring at the genetic level. This phenotypic and genotypic disparity may account in part for the failure to establish effective screening and surveillance protocols, based on the traditional clinical and microscopic examination. The tumor markers are playing an increasingly important role in cancer detection and management. These laboratory-based tests are potentially useful in screening for early malignancy, aiding in cancer diagnosis, determining prognosis, surveillance following curative surgery for cancer, up-front predicting drug response or resistance, and monitoring therapy in advanced disease. A systematic review of the literature was performed based on the English titles listed in the PubMed, EBSCO, Cochrane, Science Direct, ISI web Science, and SciELO databases using the keywords. Abstracts and full-text articles were assessed. This article may help to identify the potential biomarkers for screening and the molecular pathology analysis in the high-risk patients with the OSCC.


Santarelli A, Lo Russo L, Bambini F, Campisi G, Lo Muzio L. New perspectives in medical approach to therapy of head and neck squamous cell carcinoma. Minerva Stomatol 2009;58:445-52.  Back to cited text no. 1
Pathak KA, Al Hajjaj H, Viallet NV, Sutherland DS, Kerr PD, Nason RW. Squamous cell carcinoma of the oropharynx: Influence of site of primary tumor. Oral Abstr 2009; Suppl 3 (1):73.  Back to cited text no. 2
Wu JY, Yi C, Chung HR, Wang DJ, Chang WC, Lee SY, et al. Potential biomarkers in saliva for oral squamous cell carcinoma. Oral Oncol 2010;46:226-31.  Back to cited text no. 3
Malati T. Tumour markers: An overview. Indian J Clin Biochem 2007;22:17-31.  Back to cited text no. 4
Palmisano WA, Divine KK, Saccomanno G, Gilliland FD, Baylin SB, Herman JG, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 2000;60:5954-8.  Back to cited text no. 5
Hoque MO, Begum S, Topaloglu O, Jeronimo C, Mambo E, Westra WH, et al. Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res 2004;64:5511-7.  Back to cited text no. 6
Nunes DN, Kowalski LP, Simpson AJ. Detection of oral and oropharyngeal cancer by microsatellite analysis in mouth washes and lesion brushings. Oral Oncol 2000;36:525-8.  Back to cited text no. 7
Lee A, Kim Y, Han K, Kang CS, Jeon HM, Shim SI. Detection of tumor markers including carcinoembryonic antigen, APC, and cyclin D2 in fine-needle aspiration fluid of breast. Arch Pathol Lab Med 2004;128:1251-6.  Back to cited text no. 8
Lehto VP, Pontén J. Tumor markers in human biopsy material. Acta Oncol 1989;28:743-62.  Back to cited text no. 9
Rassekh CH, Johnson JT, Eibling DE. Circulating markers in squamous cell carcinoma of the head and neck: A review. Eur J Cancer B Oral Oncol 1994;30B: 23-8.  Back to cited text no. 10
Chan DW, Sell S. Tumor markers. In: Burtis CA, Ashwood ER, editors. Tietz's Textbook of Clinical Chemistry. 2nd ed. Philadelphia: WB, Saunders; 1994. p. 897-925.  Back to cited text no. 11
William B, Ronald BH. Characteristics of the Ideal Tumor Marker in Hollandfrei Cancer Medicine. 6th ed. Hamilton, (ON): BC, Decker; 2003.  Back to cited text no. 12
Jiang J, Park NJ, Hu S, Wong DT. A universal pre-analytic solution for concurrent stabilization of salivary proteins, RNA and DNA at ambient temperature. Arch Oral Biol 2009;54:268-73.  Back to cited text no. 13
Wong DT. Salivary diagnostics powered by nanotechnologies, proteomics and genomics. J Am Dent Assoc 2006;137:313-21.  Back to cited text no. 14
Shah FD, Begum R, Vajaria BN, Patel KR, Patel JB, Shukla SN, et al. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian J Clin Biochem 2011;26:326-34.  Back to cited text no. 15
Baum BJ. Principles of saliva secretion. Ann N Y Acad Sci 1993;694:17-23.  Back to cited text no. 16
Krishna Prasad RB, Sharma A, Babu HM. An insight into salivary markers in oral cancer. Dent Res J (Isfahan) 2013;10:287-95.  Back to cited text no. 17
Streckfus CF, Dubinsky WP. Proteomic analysis of saliva for cancer diagnosis. Expert Rev Proteomics 2007;4:329-32.  Back to cited text no. 18
Streckfus C, Bigler L, Tucci M, Thigpen JT. A preliminary study of CA15-3, c-erbB-2, epidermal growth factor receptor, cathepsin-D, and p53 in saliva among women with breast carcinoma. Cancer Invest 2000;18:101-9.  Back to cited text no. 19
Bretschneider N, Brand H, Miller N, Lowery AJ, Kerin MJ, Gannon F, et al. Estrogen induces repression of the breast cancer and salivary gland expression gene in an estrogen receptor alpha-dependent manner. Cancer Res 2008;68:106-14.  Back to cited text no. 20
Chen DX, Schwartz PE, Li FQ. Saliva and serum CA 125 assays for detecting malignant ovarian tumors. Obstet Gynecol 1990;75:701-4.  Back to cited text no. 21
Schapher M, Wendler O, Gröschl M, Schäfer R, Iro H, Zenk J. Salivary leptin as a candidate diagnostic marker in salivary gland tumors. Clin Chem 2009;55:914-22.  Back to cited text no. 22
You XY, Jiang J, Yin FZ. Preliminary observation on human saliva alpha-fetoprotein in patients with hepatocellular carcinoma. Chin Med J (Engl) 1993;106:179-82.  Back to cited text no. 23
Wong DT, Zhang L, Farrell J, Zhou F, Elashoff D, Gao K, et al. Salivary biomarkers for pancreatic cancer detection [abstract]. J Clin Oncol 2009;27 Suppl 15S: 4630.  Back to cited text no. 24
Lodhi FB, Ali M, Iftikhar, Hussain R. Serum tumor markers. Prof Med J 2006;13:110.  Back to cited text no. 25
Zhang L, Rosin MP. Loss of heterozygosity: A potential tool in management of oral premalignant lesions? J Oral Pathol Med 2001;30:513-20.  Back to cited text no. 26
Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, et al. Genetic progression model for head and neck cancer: Implications for field cancerization. Cancer Res 1996;56:2488-92.  Back to cited text no. 27
Lee JJ, Hong WK, Hittelman WN, Mao L, Lotan R, Shin DM, et al. Predicting cancer development in oral leukoplakia: Ten years of translational research. Clin Cancer Res 2000;6:1702-10.  Back to cited text no. 28
Partridge M, Pateromichelakis S, Phillips E, Emilion GG, A'Hern RP, Langdon JD. A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization. Cancer Res 2000;60:3893-8.  Back to cited text no. 29
Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000;6:357-62.  Back to cited text no. 30
Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, et al. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 2000;287:2017-9.  Back to cited text no. 31
Liao PH, Chang YC, Huang MF, Tai KW, Chou MY. Mutation of p53 gene codon 63 in saliva as a molecular marker for oral squamous cell carcinomas. Oral Oncol 2000;36:272-6.  Back to cited text no. 32
Tilakaratne WM. Oral cavity and major and minor salivary glands. In: The Cancer Handbook. 2nd ed. United States: John Wiley and Sons Ltd.; 2007. p. 1-15.  Back to cited text no. 33
Rosas SL, Koch W, da Costa Carvalho MG, Wu L, Califano J, Westra W, et al. Promoter hypermethylation patterns of p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase in tumors and saliva of head and neck cancer patients. Cancer Res 2001;61:939-42.  Back to cited text no. 34
Zhong LP, Chen GF, Xu ZF, Zhang X, Ping FY, Zhao SF. Detection of telomerase activity in saliva from oral squamous cell carcinoma patients. Int J Oral Maxillofac Surg 2005;34:566-70.  Back to cited text no. 35
Vielba R, Bilbao J, Ispizua A, Zabalza I, Alfaro J, Rezola R, et al. p53 and cyclin D1 as prognostic factors in squamous cell carcinoma of the larynx. Laryngoscope 2003;113:167-72.  Back to cited text no. 36
Shpitzer T, Hamzany Y, Bahar G, Feinmesser R, Savulescu D, Borovoi I, et al. Salivary analysis of oral cancer biomarkers. Br J Cancer 2009;101:1194-8.  Back to cited text no. 37
Chen XQ, Stroun M, Magnenat JL, Nicod LP, Kurt AM, Lyautey J, et al. Microsatellite alterations in plasma DNA of small cell lung cancer patients. Nat Med 1996;2:1033-5.  Back to cited text no. 38
Park NJ, Zhou H, Elashoff D, Henson BS, Kastratovic DA, Abemayor E, et al. Salivary microRNA: Discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 2009;15:5473-7.  Back to cited text no. 39
Li Y, St John MA, Zhou X, Kim Y, Sinha U, Jordan RC, et al. Salivary transcriptome diagnostics for oral cancer detection. Clin Cancer Res 2004;10:8442-50.  Back to cited text no. 40
Crocker J, Murray PG, editors. Molecular Biology in Cellular Pathology. Chichester: John Wiley and Sons Ltd.; 2003. p. 352.  Back to cited text no. 41
Denny P, Hagen FK, Hardt M, Liao L, Yan W, Arellanno M, et al. The proteomes of human parotid and submandibular/sublingual gland saliva collected as the ductal secretions. J Proteome Res 2008;7:1994-2006.  Back to cited text no. 42
Hu S, Arellano M, Boontheung P, Wang J, Zhou H, Jiang J, et al. Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res 2008;14:6246-52.  Back to cited text no. 43
Lehrer RI, Ganz T, Selsted ME. Defensins: Endogenous antibiotic peptides of animal cells. Cell 1991;64:229-30.  Back to cited text no. 44
Mizukawa N, Sugiyama K, Fukunaga J, Ueno T, Mishima K, Takagi S, et al. Defensin-1, a peptide detected in the saliva of oral squamous cell carcinoma patients. Anticancer Res 1998;18:4645-9.  Back to cited text no. 45
Franzmann EJ, Reategui EP, Pedroso F, Pernas FG, Karakullukcu BM, Carraway KL, et al. Soluble CD44 is a potential marker for the early detection of head and neck cancer. Cancer Epidemiol Biomarkers Prev 2007;16:1348-55.  Back to cited text no. 46
St John MA, Li Y, Zhou X, Denny P, Ho CM, Montemagno C, et al. Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2004;130:929-35.  Back to cited text no. 47
Markopoulos AK, Michailidou EZ, Tzimagiorgis G. Salivary markers for oral cancer detection. Open Dent J 2010;4:172-8.  Back to cited text no. 48
Kang MS, Oh JS, Kim HJ, Kim HN, Lee IK, Choi HR, et al. Prevalence of oral microbes in the saliva of oncological patients. J Bacteriol Virol 2009;39:277-85.  Back to cited text no. 49
Mager DL, Haffajee AD, Devlin PM, Norris CM, Posner MR, Goodson JM. The salivary microbiota as a diagnostic indicator of oral cancer: A descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. J Transl Med 2005;3:27.  Back to cited text no. 50