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An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists

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Year : 2021  |  Volume : 25  |  Issue : 2  |  Page : 332-345

Recognizing the salivary panomics for the clinical application in oral potentially malignant disorders

Department of Oral Medicine and Radiology, VMS Dental College, Vinayaga Mission's Research Foundation, Salem, Tamil Nadu, India

Date of Submission15-Sep-2020
Date of Decision20-Jan-2021
Date of Acceptance24-Apr-2021
Date of Web Publication31-Aug-2021

Correspondence Address:
Kavitha Muthu
Department of Oral Medicine and Radiology, VMS Dental College, Vinayaga Mission's Research Foundation, Salem, Tamil Nadu 641 402
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-029X.325237

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Oral cancer arises as a result of multistep carcinogenic progress from precursor lesion to oral squamous cell carcinoma through collective mutational process occur in the stem cells of mucosal epithelium. The detection of such oral potentially malignant disorders (OPMDs)/cancer in subclinical level will greatly improve the prognosis of a patient. The highly specific and sensitive salivary biomarkers have functioned in detection, prediction, surveillance and therapeutic monitoring of the diseases of interest. The aim of the review is to appraise various salivary biomarkers for the clinical utility in OPMDs. An electronic web-supported search was performed via PubMed, ScienceDirect and Google Scholar search engine since the year 2015–2019. A total of 28 research articles were selected for the review after screening and assessment. The various genomic, transcriptomic, proteomic, metabolomic and miscellaneous markers were analyzed and their characteristics and clinical application in OPMD patients were discussed. miR-21, miR-31, miR-84, H3F3A mRNA + IL-8P, matrix metalloproteinase-9, chemerin, tumor necrosis factor-alpha, cytokeratin-10, ornithine + O-hydroxybenzoate + R5F, 8-hydroxy-2-deoxyguanosine, malondialdehyde, Vitamin E and Vitamin C are identified as potential markers for OPMD patients. Scientifically validated, reliable and economical clinical biomarkers in OPMDs would serve as evidence-based treatment from patient point of view. Further longitudinal studies are needed to verify the accuracy and validate the applicability of these diagnostic/prognostic markers. Saliva has been reported as a valuable noninvasive valuable tool in biomarker identification. Recent advancements in salivary biomarker identification techniques lead to various potential biomarkers with precise outcome. The utilization of these biomarkers for the clinical application in OPMDs depends on the feasibility and personal choice of the clinician.

Keywords: Oral potentially malignant disorder biomarkers, salivary biomarkers, salivary panomics

How to cite this article:
Muthu K, Narayanan M. Recognizing the salivary panomics for the clinical application in oral potentially malignant disorders. J Oral Maxillofac Pathol 2021;25:332-45

How to cite this URL:
Muthu K, Narayanan M. Recognizing the salivary panomics for the clinical application in oral potentially malignant disorders. J Oral Maxillofac Pathol [serial online] 2021 [cited 2021 Dec 2];25:332-45. Available from: https://www.jomfp.in/text.asp?2021/25/2/332/325237

   Introduction Top

Oral potentially malignant disorder (OPMD) has an increased risk for malignant transformation (MT) which could be an epithelial lesion or a disorder. They are considered as the precursor lesion for oral squamous cell carcinoma (OSCC). The commonly encountered OPMD lesions are leukoplakia, lichen planus, oral submucous fibrosis, erythroplakia and erythroleukoplakia.[1] The global prevalence of OPMD is 4.5% approximately, and a study revealed that the MT in OPMD is 4.32%, with a range of 6–67-month follow-up in a Taiwanese cohort.[2] The predictors of OPMD turning into malignancy would include clinical parameters, histopathological examination and molecular diagnostic methods. According to clinical parameters, patients with history of alcohol, betel-quid chewing and family history of oral cancer are having increased risk for malignancy. The appearance of verrucous hyperplastic leukoplakia, erythroplakia, multiple sites of occurrence and large size has increased risk than other lesions.[3] Histopathology grading of dysplasia of the OPMD also predicts the cancer risk. Severe dysplastic lesions are considerably having high-risk cancer transformation. Right now, this is the validated diagnostic procedure for the detection of MT in OPMDs.[4]

The molecular-level biomarkers have been extensively studied using whole blood, serum, plasma, tissues, cell lines and saliva. Biomarkers being product of malignant cells, they may also serve as a target for intervention of therapy to prevent disease progression. These include genetic and epigenetic markers which would be helpful in early prediction of cancer in high-risk groups as well as screening of such lesions over a period of time. Serum and salivary biomarkers are also beneficial for convenient disease monitoring, and quantifying them on a scale makes it easier to compare levels during follow-up.[5]

The oral biofluid/saliva as an easily available noninvasive sample makes it striking option for diagnosing, monitoring and prognosis of various human ailments. The reported advantage of salivary sample is being feasible application in the pediatric groups, disabled persons and in frequent follow-up procedures. It would be an excellent alternative when biopsy specimen is insufficient for further processing.

Unlike other areas, oral cavity provides the visibility for the follow-up and predicts the cancer in high-risk OPMD patients. Regardless of the new invention of early diagnostic and advanced therapeutic techniques for OSCC, the 5-year survival rate remains low (50%–60%).[6] Typically, the symptom presentation of OPMD patients to the clinic and the confirmatory diagnosis proceed long time. In India, 80% of OSCCs are reported to have OPMD and majority of the patients are having habit-associated etiology, i.e., tobacco, smoking and alcohol.[7] The early detection of OSCC in high-risk group of OPMD would greatly improve the prognosis of the patient. The treatment decisions can also be quickly made according to the diagnosis and risk for MT. A reliable, cost-effective, precise and noninvasive biomarker would also be useful for cancer screening/preventive programs.

   Materials and Methods Top

  • Study design: Systematic review
  • Objective of the study: Salivary biomarkers for diagnosing OPMDs/predicting early oral cancer in OPMDs
  • Materials of the study: Scientific articles
  • Units of analysis:

The natural history and types of OPMD, different types of salivary biomarkers and their characteristics, the molecular method of identification of salivary biomarkers in OPMD, parameters such as P values, specificity, sensitivity, receiver operating curve (ROC) and area under curve (AUC) report of the biomarkers.

Study criteria

Inclusion criteria

  • 2015–2019 English language studies
  • Studies using human saliva for biomarker study in OPMDs
  • Descriptive/observational studies
  • Analytical/observational studies
  • Diagnostic tests.

Exclusion criteria

  • Books/book chapters
  • Other language studies
  • Studies with nonhuman samples
  • Studies using oral rinses
  • Metagenomic/metaproteomic studies of oral microbiota.

Search strategy

An electronic web-supported search was performed via PubMed, Google Scholar and ScienceDirect search engine from the year 2015–2019. The search words such as oral potentially malignant disorder or salivary biomarkers, leukoplakia and salivary biomarkers, erythroplakia and salivary biomarkers, submucous fibrosis or salivary biomarkers, lichen planus and salivary biomarkers, OSCC and salivary biomarkers and human saliva were used. The supplementary data were collected from reference list of articles and other relevant articles. By using filters, articles were sourced from the year 2015–2019. The relevant article has been chosen by reading the title and abstract of the article. After removing the duplication of articles and repeated studies, the systematic review was done with the abstracts of all sourced articles and full text of available ones. The article selection process is explained in [Figure 1].
Figure 1: Flowchart

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   Results Top

The results are tabulated in [Table 1] and [Table 2].[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34]
Table 1: Summary of salivary genomic biomarkers in oral potentially malignant disorder

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Table 2: Summary of Sensitivity, Specificity and AUC values of bio markers in OPMDs

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It describes the patient/study demographics.

Types of OPMD, comparison groups and cohort size.

Types of biomarkers (genomics/transcriptomics/proteomics/metabalomics).

Sample collection and diagnostic techniques.

Clinical inference of the study

The role of biomarkers in carcinogenesis

[Figure 2] and [Figure 3] depict the types of OPMD and the various biomarker studies in order.
Figure 2: Types of oral potentially malignant disorders included in the review

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Figure 3: Types of salivary panomics assessed in this review

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   Discussion Top

OPMDs being a sign for foreseen malignancy, particularly in high-risk groups, the early detection of MT helps the clinician to start more aggressive therapy and intensive follow-up to give better prognosis for the patient. The latest study reported that the MT in OPMD varies between 1.4% and 36%.[35] Various elements play a role in progression of OPMD into malignancy such as population, gender, habits and grade of dysplasia. A significant number of lesions are reported to be malignant even before the histologic changes of dysplasia.[1] In addition, patients with family history of OSCC with high-risk OPMDs and patients with possibility for second primary can also be benefited with early diagnosis. It will greatly improve the morbidity and the economic burden of a patient.

Biomarkers being products of malignant cells, they may also serve as a target for intervention of therapy to prevent disease progression.[36] Several standard methods with optimum protocol are available for the collection of whole-mouth saliva in a passive unstimulated manner, and various types of salivary collection devices are also available in the market. The collected saliva can be placed in ice or instant frozen in liquid nitrogen and centrifugation done at + 4°C to remove insoluble materials/debris, and the supernatant saliva can be stored at − 80°C till it gets analyzed.[37] [Table 3] shows the various study methods to detect and quantify the salivary biomarkers.[38]
Table 3: Study methods to detect and quantify a salivory bio markers

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The data from the available literature from the year 2015–2019 have been reviewed for the identification of potential salivary biomarkers for screening/diagnosing PMDs. Most of the studies have included oral lichen planus, leukoplakia and oral submucous fibrosis as the study sample.

The comparison group of the study also varies from healthy controls and OSCC patients. Few studies have also included high-risk group (smokers/drinkers) and disease controls such as aphthous stomatitis and persistent suspicious oral lesions as the study sample.

The biomarker of interest in each study depends on the demographical factors such as ethnic group, age, gender and individual habits. Among OPMDs, the etiopathogenesis and prevalence of the particular disease and the clinical course of the disease determine the selection of biomarker in each study.

To minimize the bias in salivary bio marker study the following factors like the methods of collection of sample, sample processing, time of collection, blinding of samples while measurement, the biomarker identification methods, sample attrition, other confounding factors, study follow-up, validation and the methods of statistical analysis has to be considered carefully.

This paper includes studies of individual and combined OPMDs. Biomarkers in OPMD can be used as diagnostic, prognostic or disease-monitoring purposes. In general, the control subjects were normal subjects or OSCC patients. Studies among the various histologic grades of OPMD would be useful for disease-monitoring purposes.

Since there is lot of heterogeneity among the selected studies, the results were analyzed and concluded according to their statistically significant results, follow-up periods, validation methods and specificity, sensitivity and AUC analysis as they highlight the study accuracy and important appraise of biomarker performance in distinguishing OPMDs from controls.

In general, salivary genomic studies reveal the genetic expression such as miRNA changes, DNA hypermethylation/hypomethylation, gene polymorphism, histone acetylation/deacetylation, loss of imprinting and chromosome inactivation. Promoter hypermethylation of DNA and miRNA studies in OPMDs provided promising results for their diagnostic and predictive values. The long noncoding RNA (lncRNA), salivary exosomal studies, studies on salivary extracellular vesicle, circulating cell-free DNA and circulating tumor DNA expression studies are the emerging areas in salivary genomic studies.

The miRNA studies revealed the upregulation or downregulation of various miRNA expressions in the particular disease of interest. Only two studies have come up with AUC value analysis. Hung et al. recommended that miR-21 and miR-31 were significantly higher in OPMD patients than in controls. This study also compared these miR expressions in tissue sample with a follow-up period of 820 days. It only mentions the sensitivity of the markers.[10] Zahran et al. in their studies suggested that miRNA-184 is significantly increased in OPMD with dysplasia patients when compared to normal and OSCC patients with maximum sensitivity (80%) and specificity (75%) and a high AUC value (0.86). This study also includes recurrent aphthous stomatitis as one of the disease control groups and found no differences from healthy control group. This study has a follow-up period of 3 years.[13] These three miRNA studies gave promising results and can be clinically utilized as potential markers in OPMD patients.

Salivary transcriptomic analysis takes accounts of RNA biomarker analysis of particular transcripts of genes. Various mRNA biomarkers and their predictive value have been studied individually and as a panel of markers. The significantly higher expression of mRNA and protein panel of H3F3A + IL-8 biomarkers could have a great AUC value of 0.752 in differentiation between OSCC and PMOD patients.[15]

Salivary proteomic studies include the study of either individual proteins of interest with total protein analysis or panel of proteins and peptides, and the particular proteins could be further validated.

Tumor necrosis factor-alpha (TNF-α) receptors are expressed on both epithelial and stromal cells. TNF-α is a pro-inflammatory cytokine that has both pro- and antitumorigenic effects. The cytotoxic effect is through necrosis which inhibits tumor progression. It can also stimulate angiogenesis, proliferation, migration and survival of tumor cells in cancer. Deepthi et al. found that there were extermely significant differences across three groups with elevated TNF-α expression from controls to leukoplakia to OSCC. The sensitivity is 90% and specificity 95%, with the 0.968 AUC value between leukoplakia and healthy control.[17]

Within the proteomic markers discussed, chemerin and matrix metalloproteinase (MMP)-9 also showed a significantly higher level, satisfactory AUC with high sensitivity and specificity in distinguishing OSCC from oral potentially malignant lesions. Chemerin is commonly witnessed in adipose tissue, fibroblast, endothelium and keratinocytes. Various studies stated that chemerin is a multifunctional adipokine which participates in regulating angiogenesis, inflammation and cell proliferation. MMP-9 is the largest member among the 26 members of MMP gene family. By degrading type IV collagen, fibronectin and elastin and also through regulation of angiogenesis, MMP-9 plays a major role in the pathogenesis of tumor.[20]

Camisasca et al. in their study suggested the presence of another interesting protein cytokeratin-10 (CK-10) fragment in all leukoplakia samples with decreased folds of cystatin-A when compared to control with a mean of 2.73-year follow-up. Further studies are needed to validate the use of CK-10 as a potential biomarker in predicting the progress of malignancy in leukoplakia. The tissue immunohistochemistry confirmed the presence of CK-10 in the superficial layers of the Oral Leukoplakia (OL) patients, which verifies the readily available of this protein in saliva. This was absent in the control group. However lower level of cystation SN indicates that cysteine protease may be involved in this cleavage.[21]

Salivary metabolomics is the study of metabolites that are small molecules released during metabolism that can provide the information regarding the early changes associated with the OPMDs.

This review includes only one study of salivary metabolomics. The study results revealed significantly decreased arginine, carnitine, ornithine, o-hydroxybenzoate, N-acetylglucosamine-1-phosphate and ribose-5-phosphate levels in the OSCC/oral epithelial dysplasia group than in persistent suspicious oral mucosal lesions (PSOMLs). The decrease in the R5P, one of the intermediate metabolites in the pentose phosphate pathway, specified a Warburg effect. The precursors of polyamines such as arginine and ornithine are intermediate metabolites in the urea cycle and are considered as a biomarker in various cancers. Since the increased polyamines are the indicators of the reduced ornithine and arginine, the study results were reasonable. The ROC analysis of the combined ornithine + O-hydroxybenzoate + R5F metabolites has shown that the AUC was sufficient to discriminate OSCC/Oral Epithelial Dysplasia from PSOML groups.[27]

The miscellaneous marker includes inflammatory/oxidative biomarkers and markers associated with anaerobic glycolysis. The reactive oxygen and nitrogen species give rise to oxidative damage to DNA and could be crucial in carcinogenesis and mutagenic. The UV light exposure, radiation and reactive oxygen and nitrogen species lead to the creation of 8-hydroxy-2-deoxyguanosine (8-OHdG). The membrane phospholipids are injured by the reactive oxygen and nitrogen species and identified as lipid peroxidation with malondialdehyde (MDA), a well-known biomarker of cell exposed to oxidative stress. In addition, the cytotoxic nature of MDA is reported to be responsible for tumor promotion and carcinogenesis. In contrast, Vitamin C and Vitamin E are accounted for defensive role against oxidative harm to DNA.

The salivary levels of 8-OHdG and MDA were significantly higher in OSCC, while Vitamin C and Vitamin E levels were decreased pursued by advanced phases of precancer patients compared to the early phase patients. The levels of 8-OHdG and MDA were significantly higher with lower levels of Vitamin C and Vitamin E in lichen planus, leukoplakia and submucous fibrosis patients compared with healthy controls. The combination of markers has high specificity (80%) and sensitivity (80%) when compared to individual biomarker approach.[32]

The age, gender, ethnic background, geographic location, dietary factors and medications taken can also influence the outcome of biomarker research. Other important confounding factors in biomarker studies are other associated mucosal inflammatory conditions, nonneoplastic systemic diseases and/or systemic cancers that can influence the outcome of study variables. In order to circumvent these factors, a proper study design, consistent research method should be planned and implemented accordingly.[39]

The majority of the selected papers showed statistically significant results within the study limits. Few studies have come up with sensitivity and specificity with AUC characteristics in OPMD patients as diagnostic/prognostic applications. Studies among different grades/different clinical types of OPMD were less.

Biomarkers with high sensitivity, specificity and optimum AUC values are considered as potential markers as a diagnostic tool. The physician's choice of biomarker selection to differentiate OPMDs from controls depends on these remarks and the practicality. Regarding the validation of biomarkers, different study methods can be applied for the same marker to arrive at reliable results. The studies can be repeated on different ethnic cohorts with various geographic conditions. Large-scale studies would also be helpful to validate the biomarkers of interest. Regarding OPMD, more longitudinal studies with uniform study methodology are needed for further validation.

The biomarker identity in OPMD depends on the individual lesion etiology, molecular biology and genetic behavior of the disorder. Hence, the biomarker of interest also varies in each disorder. The main purpose of a reliable biomarker in OPMD is early detection of the disease progress and cancer prediction. A reliable, precise and valid panel of biomarkers for uniform application in various high-risk OPMDs in detecting MT is the need of hour.

The painless, quick and easily accessible panel of salivary biomarkers with the scientific credential for clinical/individual application in early diagnosis of oral cancer is the need of an hour. If a panel of biomarkers would be applicable for early detection of cancer in OPMD, it would also serve as an evidence-based treatment for the patients as well as it greatly reduces the psychological/economic burden of the patient.

The ultimate aim of any biomarker study is the development of point of care-monitoring system to deliver feasible patient care either clinical or personal monitoring. The integrative panoramic approach extends its anticipation to the invention of novel biomarkers and targeted therapeutics which leads to the new precision medicine era with enhanced patient care in the health-care system.

   Conclusion Top

The early intervention is possible, if the genetic or epigenetic level markers are identified in early stages of OPMDs before the advanced clinical manifestation would emerge. The diagnostic ability of the biomarkers in OPMD is clearly evident from various studies, and these potential biomarkers can definitely delineate the OPMD patients from either normal or OSCC patients. The success of prediction/prognostic biomarker depends on the identification and validation of early MT in OPMD patients. For the disease-monitoring purposes, the expression of particular marker over a period of time would be an indicator for patient counseling and follow-up. The painless, quick and easily accessible panel of salivary biomarkers with the scientific credential for clinical/individual application in early diagnosis of oral cancer is the need of hour. The salivary biomarkers would also serve to monitor tumor heterogeneity over a period of time on a scale which is difficult to achieve with biopsy alone. The application of oral biofluid as a biomarker in detecting early oral cancer diagnosis would be more valuable in OPMD cases rather than Stage III and Stage IV oral cancer since the major side effect of postradiation therapy patients is xerostomia. Genomic salivary marker studies to detect long noncoding RNA and promoter hypermethylation of DNA and other genomic studies such as salivary exosomal study, extracellular vesicle study, circulating tumor cells and cell-free DNA studies were relatively less in OPMD patients. This could be the future areas of interest for the researchers. It is advisable to perform more longitudinal studies involving all the types of OPMDs for the homogeneous application in early cancer diagnosis.

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Conflicts of interest

There are no conflicts of interest.

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