[Downloaded free from http://www.cancerjournal.net on Thursday, January 23, 2020, IP: 186.236.73.58] Review Article A review on oral cancer biomarkers: Understanding the past and learning from the present ABSTRACT Arvind Babu Biomarkers are broadly classified as genomic, proteomic, or metabolomic. Molecular biology and oncology research studies on Rajendra oral cancer biomarkers focus on identifying key biological molecules or markers that could be linked to cancer development, risk Santosh, assessment, screening, recurrence prediction, indicating prognosis, indicating invasion/metastasis and monitoring therapeutic Thaon Jones, responses of cancer. Cluster of differentiation factor 34 is a salivary biomarker that can identify recurrence potential of oral squamous John Harvey1 cell carcinoma (OSCC). Integrin α3 and integrin β4 are genomic biomarkers that are helpful in estimating the risk of regional and Dentistry Programme, hematogenous dissemination of malignant oral squamous cells. Other examples are vascular endothelial growth factor, B‑cell Faculty of Medical lymphoma‑2, claudin 4, yes‑associated protein 1 and MET proto‑oncogene, and receptor tyrosine kinase, which are genomic Sciences, The biomarkers that are used to predict radio‑resistance in OSCC tissue. The present article reviews the clinical application, methodologies University of the and steps in developing candidate biomarkers, protocols in reporting, evaluating candidate biomarkers, and challenges in biomarker West Indies, Mona, research with a focus OSCC. Kingston, Jamaica, West Indies, 1Department of Periodontology, KEY WORDS: Biomarkers, evaluation, oral cancer, oral squamous cell carcinoma, reporting School of Dentistry, Meharry Medical College, Nashville, INTRODUCTION provide valuable diagnostic data, i.e., biomarkers, Tennessee, United States of America on the cancer disease process. The National Cancer Carcinogenesis is a complex process that occurs Institute has defined “biomarker” as a biological For correspondence: at the phenotype and genotype levels. Cancer molecule found in blood, other body fluids, or Dr. Arvind Babu development is driven by the accumulation of genetic tissues that is a sign of a normal or abnormal Rajendra Santosh, Lecturer and Research [3] and epigenetic changes that disturb the homeostatic process, or of a condition of disease such as cancer. Coordinator – Dentistry equilibrium between cell proliferation and cell Biomarkers play an important role in distinguishing Programme, Faculty death.[1] The molecular level changes that occur between the presence or absence of disease. The of Medical Sciences, in carcinogenesis are: (i) cancer cell proliferation underlying tissue changes in the disease process The University of the West Indies, Mona, without external stimuli, (ii) insensitivity to could be categorized as genomic, proteomic, or Kingston, Jamaica, inhibitory growth signals, (iii) evasion of apoptosis metabolomic expressions [Figure 1]. Biomarkers West Indies. or cell death mechanisms and/or activation of include nucleic acids, proteins, peptides, enzymatic E‑mail: anti‑apoptotic genes, (iv) unlimited replicative arvindbabu2001@ changes, antibodies, metabolites, lipids, and gmail.com potential, (v) sustained angiogenesis, (vi) invasion carbohydrates.[4] Biomarkers can be derived from and metastasis ability, (vii) genomic instability, one, or a combination, of the following body fluids and (viii) protooncogenes mutation caused by blood, serum, plasma, body secretions (sputum, defects in DNA repair.[1] saliva), or excretions (stool, urine). Body fluids sample for biomarker investigation can be Research on cancer tissues has revealed that obtained by noninvasive, minimally invasive there may be a link between molecular level and or invasive methods.[5] Nucleic acids (DNA/RNA) Access this article online tissue level changes that drive malignant changes Website: www.cancerjournal.net DOI: 10.4103/0973-1482.176414 in the tissue and play a pivotal role in disease This is an open access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, PMID: *** [2] progression. The inference can be drawn is that tweak, and build upon the work non‑commercially, as long as the author is credited Quick Response Code: a study of the biological molecules involved in and the new creations are licensed under the identical terms. the molecular mechanism of carcinogenesis could For reprints contact: [email protected] Cite this article as: Santosh AB, Jones T, Harvey J. A review on oral cancer biomarkers: Understanding the past and learning from the present. J Can Res Ther 2016;12:486‑92. 486 © 2016 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow [Downloaded free from http://www.cancerjournal.net on Thursday, January 23, 2020, IP: 186.236.73.58] Santosh, et al.: Oral cancer biomarkers extracted from blood, saliva, oral exfoliative cells, or buccal predicting tool for recurrent cases of OSCC.[10] Genomic smear cells are instrumental in identifying mutations and biomarkers such as integrin α3 and integrin β4 have been will help to correlate and confirm the diagnosis, monitor positively correlated with distant metastases and prognosis the disease progression, or act as prognostic indicators in of tumors.[11] Sixty vascular endothelial growth factor, B‑cell treatment.[6] lymphoma‑2, claudin 4, yes‑associated protein 1 and MET proto‑oncogene, and receptor tyrosine kinase were suggested CLINICAL APPLICATIONS AND CONSIDERATIONS OF ORAL as a novel group of biomarkers that function as therapeutic CANCER BIOMARKERS monitors and radioresistance predictors in OSCC patients.[12] Hu et al. reported immunoassay validation of salivary proteins Biomarkers can be used for patient assessment in multiple such as Mac‑2‑binding protein (M2BP), profilin, CD59, MRP14, clinical settings. They can be used for estimating disease risk, catalase, histone H1, S100A12, rat sarcoma viral oncogene screening for occult primary cancers, distinguishing benign homolog (Ras)‑related protein Rab‑7, moesin, involucrin, from malignant findings/one type of malignancy from another, S100 calcium binding protein P (S100P), and hematopoietic determining prognosis, acting as predictors/screening, and lineage cell‑specific protein are differentially abundant in [13] monitoring disease status. Biomarkers can be used to either OSCC and healthy control subjects. Aberrant expression detect recurrence or determine progression/response to of miR‑375, miR‑200a, and miR‑200c‑144 methylation was therapy. The determination of a patient’s risk of developing initially identified in OSCC and suggested as a potential clinical [14] oral cancer is helpful if risk reduction strategies or screening application for OSCC diagnosis. The clinical significance of have been effective. These strategies when applied to high‑risk the above mentioned oral cancer biomarkers is summarized groups are much more efficient than wholesale application to in Table 1. the entire population.[7] Biomarkers can be used as screening tools in healthy Salivary biomarkers such as L‑phenylalanine serve as individuals and in patients who are clinically or histologically negative for oral cancer. Screening and early diagnosis of oral screening biomarkers and help in the early diagnosis and cancer are a useful and important risk‑reduction strategy. monitoring of oral squamous cell carcinoma (OSCC).[8] Cloning Other strategies are lifestyle changes, habit cessation, and of an acidic laccase gene 2 is a proteomic biomarker that prophylactic treatment in cancer prevention, which increase is used to differentiate between squamous cell carcinoma the survival rate of patients. In 2014, Wang et al. successfully and adenocarcinoma.[9] The angiogenetic marker cluster isolated potential salivary biomarkers for the early diagnosis of differentiation factor 34 (CD34) serves as an important of OSCC. Their study investigated eight up‑regulated and six down‑regulated groups of salivary metabolomic biomarkers. Their study employed an integrated separation approach of reversed phase liquid chromatography and hydrophilic interaction chromatography combined with a time‑of‑flight mass spectrometer to study the salivary metabolomic analysis methods. The results revealed that five salivary metabolomic biomarkers, propionyl choline, N‑acetyl‑L‑phenylalanine, sphinganine, phytosphingosine, and Table 1: Clinical significance of oral cancer biomarkers Clinical significance Oral cancer biomarker Reference category Screening for oral Salivary biomarkers such as Wang squamous cell L‑phenylalanine, sphinganine, et al. in 2014[8] carcinoma phytosphingosine, and S‑carboxymethyl‑L‑cysteine Differential diagnosis Proteomic marker CLAC2 Shinmura et al. in 2014[9] Recurrence potential CD34 expression Kademani marker et al. in 2009[10] Predicting prognosis Genomic biomarkers such as Nagata and distant metastasis ITGA3 and ITGB4 expression et al. in 2013[11] Predicts Genomic markers such as Akervall radio‑resistance in VEGF, BCL‑2, Claudin‑4, et al. in 2014[12] oral squamous cell YAP‑1, and c‑MET carcinoma CLAC2=Cloning of an acidic laccase gene 2, CD34=Cluster of differentiation factor 34, VEGF=Vascular endothelial growth, BCL‑2=B‑cell lymphoma‑2, YAP‑1=Yes‑associated protein 1, c‑MET=MET proto‑oncogene, receptor Figure 1: Classification of oral cancer biomarkers tyrosine kinase, ITGA3=Integrin α3, ITGB4=Integrin β4 Journal of Cancer Research and Therapeutics