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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 29  |  Issue : 4  |  Page : 300-305

Genomic Alphabets of Saliva as a Biomarker in Oral Cancer


Department of Oral Medicine and Radiology, Rajarajeswari Dental College and Hospital, Bengaluru, Karnataka, India

Date of Submission01-Aug-2016
Date of Acceptance29-Jan-2018
Date of Web Publication15-Feb-2018

Correspondence Address:
Dr. Talkad Subbaiah Mahesh Kumar
Department of Oral Medicine and Radiology, #14, Rajarajeswari Dental College and Hospital, Ramohalli Cross, Mysore Road, Bengaluru - 560 074, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.JIAOMR_90_16

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   Abstract 


Oral cancer is one of the most common cancers in the developing world with high mortality rate despite the recent advances in diagnosis and treatment. The major reason for low survival rate is late diagnosis. Salivary diagnostics is an emerging field along with the application of genomics aiding in the early detection of oral cancer. These genomic alphabets of saliva may serve as a timely, cost effective, noninvasive diagnostic medium. This article aims to discuss the role of genomic alphabets of saliva in the diagnosis of oral cancer.

Keywords: Biomarker, oral cancer, saliva


How to cite this article:
Poornima G, Mahesh Kumar TS. Genomic Alphabets of Saliva as a Biomarker in Oral Cancer. J Indian Acad Oral Med Radiol 2017;29:300-5

How to cite this URL:
Poornima G, Mahesh Kumar TS. Genomic Alphabets of Saliva as a Biomarker in Oral Cancer. J Indian Acad Oral Med Radiol [serial online] 2017 [cited 2019 Dec 15];29:300-5. Available from: http://www.jiaomr.in/text.asp?2017/29/4/300/225569




   Introduction Top


One of the major global public health problems is oral cancer which accounts for one-third of the burden of Indian subcontinent, ranking sixth among all cancers.[1],[2] The morbidity and the disappointing survival rate may be attributed to diagnostic delay as most oral cancers are asymptomatic in their initial stages.[3],[4] Oral cavity is an important part of the body; multiple structures and tissue are working in this intricate environment. Oral cancer has an increased incidence in comparison to other cancers in various anatomical sites particularly in younger individuals and women.[5] The changes in the incidence of oral cancer cannot be explained purely by tobacco and alcohol consumption, which are considered major risk factors because oral cancer may also be observed in individuals who are free of these habits.[6]

The genetic aberration of cancer cells leads to altered gene expression patterns, which can be identified long before the resulting cancer phenotypes are manifested. These changes are unique in cancer in comparison with that of normal tissue of same origin, hence, this can be utilized as molecular biomarkers.[7] The main aim of oral cancer screening is to diagnose oral cancer at an early stage for effective treatment and better prognosis. Hence, screening tests that disclose the combination of increased sensitivity and increased specificity are required; moreover, the screening tool must be sufficiently noninvasive and cost-effective and timely available to allow widespread applicability. Outstanding development of biotechnology and development in the basic understanding regarding cancer initiation and progression has empowered us in identifying tumor signatures such as oncognes and tumor suppressor gene alterations in bodily fluids that drain from the organs affected by the tumor.[8]

Application of genomics and the knowledge of the sequence of human genome have inspired numerous -omics disciplines such as proteomics, epigenomics, transcriptomomics, glycomics, and metabolomics enabling us to understand the signaling pathways of the cell and thereby provide valuable insight into the pathogenesis of disease leading to identification of new prognosticators, diagnostic markers, and therapeutic targets.[9] Biomarkers are defined as cellular, biochemical, molecular, or genetic alterations by which a normal, abnormal, or simply biologic process can be recognized or monitored. Tissues, cells, or any body fluid can be a biomarker which may be secreted by the malignancy or due to specific response of the body as a result of the malignancy.[10]

These biomarkers are important indicators of physiological or pathological conditions and provide information for the detection of early and differential markers for disease. Cognizing and assessing the importance of an individual biomarker signature may help in establishing the presence, location, and likelihood of disease. Hence, these biomarkers can be considered as valuable tools in early detection, assessing risk, diagnosis, prognosis, and disease monitoring. Of these biomarkers saliva is one such important biomarker.[11] Saliva, an unique, complex body fluid, also referred as mirror of the body health, is a biological fluid secreted by the three major salivary glands (parotid, submandibular, and sublingual), minor glands, and gingival crevicular fluid.[12],[13]

The various chemical components of saliva include water, inorganic compounds (ions), organic compounds (nonproteins and lipids), protein/polypeptides, and hormones, and an array of analytes.[12],[14] On an average, an individual salivary flow rate can vary from 0.3 to 0.7 ml of saliva per minute producing a range of 1 to 1.5 liters daily.[15],[16] Saliva is multifunctional, serving not only to facilitate digestion, swallowing, tasting, and tissue lubrication but also as a protective barrier against pathogens.[17],[18] Most common diagnostic biomarker used is serum but saliva can also be used as an alternate to serum as it has numerous advantages in comparison to serum.[19] Collection of sample is undemanding, noninvasive, safer to handle,[20] easier to ship and store, and the procedure is economical.[21] Saliva also comprises inhibitory substances as well as fewer complexes than blood.[22]

There are five major diagnostic alphabets available namely, proteins, mRNAs, miRNAs, metabolic compounds, and microbes which offer substantial advantages for salivary diagnostics because the state of the disease may be associated with detectable changes in one, but not all, dimensions.[23] The salivary biomarkers are also classified based on the mechanism of action [24] [Table 1]. Human saliva is composed of varied amount of diverse proteins, each with particular biological characteristics. Even though the proteomic content of saliva was found to be only 30% that of blood,[25] saliva is actively being investigated as a major source of protein biomarkers.[26] More than 2300 minor proteins or peptides are present in saliva defining the first salivary biomarker alphabet.[27],[28]
Table 1: Classification of Salivary biomarkers depending on the level of action at molecular level

Click here to view


Salivary proteome

The most plentiful proteins includes α-amylase, albumin, cystatins, hystatins, secretory-IgA, lactoferrin, mucins, lysozymes, proline rich proteins, statherin and transferrin which together account for more than 98% of the total salivary proteins.[29] Salivary proteins are involved in a number of metabolic pathways, including amino acid-related metabolism, carbohydrate metabolism, energy metabolism, and glycan biosynthesis, and metabolism. Interestingly, several salivary proteins were found in a few systemic diseases, such as amyloid beta A4 protein precursor (Alzheimer's), DJ-1 (Parkinson's diseases), and colon cancer secreted protein-2 (colorectal cancer). The sequential amino acid in a protein provides a link between the proteins and their respective coding genes through genetic code, and this protein complement of the genomics known as the proteome.[30]

The presence of these salivary proteomic markers in low concentration plays a major role in the discrimination of diseases. Proteomic studies of human saliva constitutes four major salivary families of specific secretory proteins – proline-rich proteins (PRPs), statherins, and cystatins – and these secretory proteins differ significantly from the host defense salivary proteins as these have a particular function in the oral cavity.[31] Even though the proteomic constituents are considered as the logical first choice as salivary diagnostic analytics, the genomic targets are considered as highly discriminatory and informative. Analysis of the salivary proteomes may reveal morbidity signatures in the early stage and monitor disease progression. Cyfra 21.1, tissue polypeptide antigen (TPA), and cancer antigen (CA125) are elevated in saliva when compared to the sera [Table 2].[32],[33]
Table 2: Classification of the salivary biomarker of oral cancer depending on the genomic alphabets

Click here to view


IL-1, IL-6 IL-8, TNF-a: These proangiogenic, proinflammatory cytokines are elevated in whole saliva of oral cancer patients and oral precancers compared to controls which suggests its utility as surrogate indicators of carcinogenic transformation from oral precancer to oral cancer. The alterations in salivary IL-6 and TNF-a might play a significant role in the development of oral leukoplakia.

Transferrin: Salivary transferrin levels were found to be in strong correlation with the size and stage of the tumor in oral cancer patients. MRP14 is overexpressed in tongue cancer, M2BP, MRP14, CD59, catalase, and profiling detects oral cancer with a sensitivity of 90% and specificity of 83% [Table 2].[34]

Salivary transcriptome

Apart from proteins, saliva also contain nucleic acids thus considered as the second alphabet,[27] Messenger (m) RNA is the direct precursor of proteins and in general the corresponding levels are correlated in cells and tissue samples. More than 3000 mRNAs are present in the human saliva, out of which 180 are common between different normal participants constituting the normal salivary transcriptome core.[35],[36]

When compared to DNA, RNA is more labile and is highly susceptible to degradation by the RNases and in cancer patients this RNase activity is elevated; thus, it is hypothesized that human mRNA could not survive extracellularly in saliva. However, with the advances in PCR, i.e., reverse transcription (RT)-PCR human mRNA can be analyzed, improving the salivary diagnostics.[34],[36] The most common mRNA significantly higher in oral cancer are IL8, IL1B, and ferritin polypeptide [Table 1] and [Table 2].[37],[38]

IL8: Interleukin 8 regulates angiogenesis, replication, calcium-mediated signalling pathway, cell adhesion, chemotaxis, cell cycle arrest, and immune response.

Transcriptome DUSP1 (dual specificity phosphatase 1): This functions by protein modification, signal transduction, oxidative stress, H3F3A H3 histone, family 3A helps in DNA binding.

IL1B (interleukin 1β): This functions as signal transduction, helps in proliferation, inflammation, and apoptosis.[37]

OAZ1 (ornithine decarboxylase antizyme 1): It is an antizyme targeting ornithine decarboxylase for degradation, subsequently inhibiting polyamine production to prevent cell proliferation. OAZ1 is also involved in other major cellular events, including differentiation and apoptosis. Recent studies have shown that OAZ1 has tumor suppressor activities and its effects on cell proliferation and differentiation have been reported in several cancer cell lines.[39] SAT (spermidine/spermine N1-acetyltransferase): Multiple abnormalities in the control of polyamine metabolism and uptake might be responsible for increased levels of polyamines in cancer cells as compared to that of normal cells.[40]

S100P (S100 calcium binding protein P): Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in-vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis, and immune evasion.[41]

Salivary microRNA

MicroRNAs (MiRNAs) are small single stranded RNA encoded by genes but are not translated into proteins. They are noncoding RNAs; instead each primary transcript (a pri-mi RNA) is processed into a short stem loop structure as a pre-miRNA and finally into a functional miRNA.[28] The study of the presence of miRNAs in human saliva is an emerging field in monitoring oral diseases with the help of salivary diagnostics. miRNAs are short noncoding RNA molecules measuring 19–25 nt in length; it was first invented in 1993 as small RNAs in Caenorhabditis elegans.[39],[42] Thereafter, miRNAs have been categorized based on the mass and the biogenesis of miRNAs and their mode of action. miRNAs binding to complementary sequences in the 3′-untranslated region (3′-UTR) of mRNAs to regulate gene expression by inhibiting protein translation and/or causing mRNA degradation, miRNAs play important roles in regulating various cellular processes such as cell growth, differentiation, apoptosis, and immune response.[43],[44]

Over 2500 miRNAs are known in the human genome and over 30% of human mRNAs are post-transcriptionally regulated by miRNAs.[42] In saliva, miRNAs were found present in both whole saliva and saliva supernatant. In addition to the combined approach of transcriptomics and proteomics, miRNA constitutes the third diagnostic alphabet in saliva. Any dysregulation in expressing these miRNA will adversely affect the cell growth and acts like a tumor suppressor or oncogene in many cancers.[45] In oral cancer, miRNAs have been shown to affect cell proliferation,[43] apoptosis,[46] and even chemotherapy resistance in OSCC patients,[47] miRNAs have also been observed in OSCC to be epigenetically regulated by DNA methylation [Table 2].[48],[49],[50]miR125, a gene, plays an important role in cell proliferation and can affect the genes involved in MAPK metabolism; miR200a genes levels are downregulated during metastasis and can be inversely correlated to the degree of invasion. miR31 gene levels are completely lost in metastatic tumors.[51]

Salivary metabolome

The collection of small molecules present in cells, tissues, organs, and biological fluids is known as metabolome, and the study of metabolome is metabolomics.[51],[52] The metabolome validates the parallel assessment of a group of endogenous and exogenous metabolites, including lipids, amino acids, peptides, nucleic acids, organic acids, vitamins, thiols, and carbohydrates and is a valuable tool for discovering biomarkers, monitoring physiological status, and making proper treatment decisions [Table 2].[53],[54] Wei et al. found that a combination of three salivary metabolites (phenylalanine, valine, and lactic acid) could distinguish OSCC patients from healthy controls with high sensitivity and high specificity (86.5% and 82.4%) and oral leukoplakia (OLK) patients (94.6% and 84.4%). Taurine and piperidine are considered as the oral cancer specific diagnostic marker.[55]

Salivary microbiome

The hard and soft tissues in the oral cavity are colonized by bacteria and gets constantly bathed in saliva.[56],[57] Oral microbiome is constituted by proportionately a minute number of bacterial phyla, of which the commonly reported abundant phyla are Firmictes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria [Table 2].[58],[59] The majority of interindividual variation has been personated because of diversity at the species or strain level.[60]Streptococcus is routinely observed to be the dominant genus in the healthy oral microbiome and commonly Prevotella, Veillonella, Neisseria, and Haemophilus dominate an individual's oral microbiome.[61] Variation is also observed in the microbial community composition of biofilms at each intraoral habitat (e.g., teeth surface, lateral and dorsal surface of tongue, etc.), most likely reflecting the different surface properties and microenvironments.[62],[63]

Even though certain studies report that 700 to 1,200 bacterial species reside in the mouth,[64],[65] investigators using next-generation sequencing (NGS) suggest that this number could be as high as 10,000.[65],[66],[67] Although many individuals shelter only about 75 to 100 predominant species of bacteria which are known to inhabit the oral cavity 35% to 50% of those have yet to be cultivated. Understanding of the alterations in the oral microbiome are related to local and systemic disorders which provides a critical input regarding disease pathogenesis, diagnosis, monitoring, and prognosis.[68] Establishing disease-specific microbiological signatures could lead to the development of simple tests targeting discriminatory microbes capable of identifying particular pathologies. Early detection, especially in population with high risk, is indicated for more expeditious therapeutic interventions which may inhibit the progression or even the onset of pancreatic cancer and other disorders, leading to more positive outcomes.[57],[69]Capnocytophaga gingivalis, Prevotella melaninogenica, and Streptococcus mitis can be used as diagnostic markers to distinguish OSCC from healthy subjects with 80% sensitivity and 82% specificity.[55]

A vast amount of Omic-based salivary data has been generated with the use of high throughput technologies, but there are some barriers to exploit such data and saliva has not been extensively interspersed in ontology and terminology resources. So recently, the Salivaomics Knowledge Base (SKB) has been established by aligning the salivary biomarker discovery. The SKB constitutes data repository, management system, and web resource fabricated to support human salivary proteomics, transcriptomics, miRNA, metabolomics, and microbiome research. The SKB provides the first web resource dedicated to salivary “omics” studies. This comprises the major data and information required to explore the biology, diagnostic potentials, pharmacoproteomics, and pharmacogenomics of human saliva.[70]

SALO is a consensus-based controlled vocabulary of terms and relations dedicated to the salivaomics domain and to saliva-related diagnostics. This is intended to meet the needs of both the clinical diagnostic community and the crossdisciplinary community of researchers.[71] With these significant advances, salivary biomarkers are developing; however some challenges exist with the use of salivary biomarkers:

  1. A lack of standardization of conditions and methods of saliva sample collection, processing, and storage
  2. Variability in the levels of potential salivary biomarkers in both non-cancerous individuals and oral cancer patients, suggest unknown confounding factors
  3. The need for further validation of oral cancer salivary biomarkers.[72]


Single biomarker detection is not effective enough for accurate diagnosis and medical decisions because of the complexity of the human biological system and the high possibility of false positive and false negative rates. The combination of multiple biomarkers could include nucleic acids which are highly discriminatory, proteins and small molecules like metabolites.[27]


   Conclusion Top


The rapid development and maturity of the genomics field along with improved biotechnology and expanded research has resulted in the emergence of different omics studies. With the advent of these salivary diagnostics, it has been an effective and promising modality for early diagnosis, prognostication, and post-therapy status monitoring in oral cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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