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


 
  Table of Contents    
ORIGINAL ARTICLE  
Year : 2020  |  Volume : 24  |  Issue : 2  |  Page : 293-307
 

Genetic predisposition and prediction protocol for epithelial neoplasms in disease-free individuals: A systematic review


Department of Oral and Maxillofacial Pathology and Microbiology, CSI College of Dental Sciences and Research, Madurai, Tamil Nadu, India

Date of Submission11-Dec-2019
Date of Decision23-Mar-2020
Date of Acceptance24-Apr-2020
Date of Web Publication09-Sep-2020

Correspondence Address:
N Gururaj
Department of Oral and Maxillofacial Pathology and Microbiology, CSI College of Dental Sciences and Research, Madurai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jomfp.JOMFP_348_19

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   Abstract 


Background: Epithelial neoplasm is an important global health-care problem, with high morbidity and mortality rates. Early diagnosis and appropriate treatment are essential for increased life survival. Prediction of occurrence of malignancy in a disease-free individual by any means will be a great breakthrough for healthy living.
Aims and Objectives: The aims and objectives were to predict the genetic predisposition and propose a prediction protocol for epithelial malignancy of various systems in our body, in a disease-free individual.
Methods: We have searched databases both manually and electronically, published in English language in Cochrane group, Google search, MEDLINE and PubMed from 2000 to 2019. We have included all the published, peer-reviewed, narrative reviews; randomized controlled trials; case–control studies; and cohort studies and excluded the abstract-only articles and duplicates. Specific words such as “etiological factors,” “pathology and mutations,” “signs and symptoms,” “genetics and IHC marker,” and “treatment outcome” were used for the search. A total of 1032 citations were taken, and only 141 citations met the inclusion criteria and were analyzed.
Results: After analyzing various articles, the etiological factors, clinical signs and symptoms, genes and the pathology involved and the commonly used blood and tissue markers were analyzed. A basic investigation strategy using immunohistochemistry markers was established.
Conclusion: The set of proposed biomarkers should be studied in future to predict genetic predisposition in disease-free individuals.


Keywords: Basic investigation, biomarker, blood markers, disease-free individual, epithelial neoplasm, genetic predisposition, immunohistochemical marker


How to cite this article:
Gowthami J, Gururaj N, Mahalakshmi V, Sathya R, Sabarinath T R, Doss DM. Genetic predisposition and prediction protocol for epithelial neoplasms in disease-free individuals: A systematic review. J Oral Maxillofac Pathol 2020;24:293-307

How to cite this URL:
Gowthami J, Gururaj N, Mahalakshmi V, Sathya R, Sabarinath T R, Doss DM. Genetic predisposition and prediction protocol for epithelial neoplasms in disease-free individuals: A systematic review. J Oral Maxillofac Pathol [serial online] 2020 [cited 2020 Sep 30];24:293-307. Available from: http://www.jomfp.in/text.asp?2020/24/2/293/294637





   Introduction Top


Epithelial neoplasm is an important global health-care problem, with high morbidity and mortality rates.[1] Cancer is a polygenic disease which shows several epigenetic factors influenced by genetic predisposition with resultant DNA damage and genomic instability. The clinical diagnosis of any epithelial malignancies depends on the signs and symptoms related to the organs affected.[2],[3] The histopathology remains the gold standard in diagnosing the disease, but immunohistochemistry is also required not only for diagnosis but also for treatment in case of undifferentiated tumors. Moreover, the overall survival rate is contingent upon staging and grading of the tumor.[5],[6],[7] Diagnosing at an advanced stage of the disease makes the removal of tumors difficult and therefore, early detection methods and prevention strategies are essential to reduce cancer mortality.

The American Society of Clinical Oncology recommends genetic counseling and testing in the setting of pre- and post-test counseling, which should include the discussion of possible risks and benefits of early detection of malignancies and prevention modalities.[5],[7] Carriers of mutations may be detected through laboratory analysis of the genetic structure of the blood and the tissue with the assistance of biomarkers.

None of the cancer susceptibility tests currently available is as yet appropriate for screening of asymptomatic individuals, however identification of a mutation in an affected member of the family may influence medical management and can be used as a critical baseline in the testing of other family members.[8],[9] Thus, the aim of this review is to analyze and summarize the results of published studies and to identify and introduce an investigation protocol for epithelial malignancies using feasible molecular markers in a disease-free individual to predict genetic predisposition.


   Materials and Methods Top


This systematic review was conducted in harmony with Preferred Reporting Items for Systematic reviews and Meta-Analyses Statement Criteria (Moher, Liberati, Tetzlaff, Altamn and PRISMA Group, 2010) [Figure 1].
Figure 1: Flowchart for the systematic review

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Inclusion criteria

In this review, we included the full papers; English literature which were published after 2000; all peer-reviewed articles; observational studies such as cohort, case–control and retrospective studies; and all the articles which used both tissue and blood as a source of biomarkers for the diagnosis and prognosis of various epithelial neoplasms. We included those articles which used blood biomarker to predict the epithelial neoplasm.

Exclusion criteria

All the duplicates and abstract-only articles were excluded. Articles which used markers only to diagnose epithelial neoplasm were also excluded.

Sources, search strategy and study selection

Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE) on Cochrane Library and Centre for Reviews and Dissemination (CRD), EMBASE, MEDLINE, SCI-EXPANDED, PUBMED and PUBMED CENTRAL were searched to identify the records pertaining to this review.

The search strategy is summarized in [Table 1]. The eligibility of this study was individually assessed in an unblinded manner by two reviewers. In the first phase of this review, all the databases were screened by the title and abstract; in the second phase, each article was read fully by each other. If discrepancies were found, they were corrected by another observer, if any.
Table 1: Systematic review search strategy for PubMed, Embase and Cochrane

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Data extraction and management

The data which were included in this review such as etiological factors, clinical signs and symptoms, diagnostic criteria, genetic predisposition, blood biomarkers, prognostic markers and immunohistochemical tissue markers were checked and reviewed by the authors. The observations were extrapolated and entered on a customized data collection format, which were tabulated in [Table 2], [Table 3], [Table 4]. The collected data were independently analyzed by each author.
Table 2: Etiological factors and clinical signs and symptoms

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Table 3: Genes and pathology involved in various epithelial neoplasms

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Table 4: Markers used by authors for various types of epithelial neoplasms

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Risk of bias and quality assessment of studies

The quality and the nature of the article were reviewed by the authors using modified Ottawa scale. After completing the data extraction, it was evaluated by the third author.


   Results Top


Author details, etiological factors and clinical signs and symptoms of the various epithelial neoplasms are tabulated in [Table 2].[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115],[116],[117],[118],[119],[120],[121],[122],[123],[124],[125],[126],[127],[128],[129],[130],[131],[132],[133],[134],[135],[136],[137],[138],[139],[140],[141],[142],[143],[144],[145],[146],[147],[148],[149]

The genes and the pathology involved in the various epithelial neoplasms are tabulated in [Table 3].[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115],[116],[117],[118],[119],[120],[121],[122],[123],[124],[125],[126],[127],[128],[129],[130],[131],[132],[133],[134],[135],[136],[137],[138],[139],[140],[141],[142],[143],[144],[145],[146],[147],[148],[149]

The biomarkers used by authors for the various epithelial neoplasms are shown in [Table 4].[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[98],[99],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115],[116],[117],[118],[119],[120],[121],[122],[123],[124],[125],[126],[127],[128],[129],[130],[131],[132],[133],[134],[135],[136],[137],[138],[139],[140],[141],[142],[143],[144],[145],[146],[147],[148],[149]


   Discussion Top


Cancer is a multistep process, which involves genetic and epigenetic factors responsible for its occurrence.[10] The etiopathogenesis of cancer can be divided into:[4]

  1. Unmodifiable intrinsic risk which refers to inevitable spontaneous mutations (inherited) that arise as a result of DNA replication
  2. Nonintrinsic risk which refers to:


    1. Modifiable exogenous/external factors (e.g., carcinogens, viruses and xenobiotic) and lifestyle factors (e.g., smoking, hormone therapy, nutrient intake and physical activity) that are exogenous to the host; and
    2. Endogenous factors that are partially modifiable and related to the characteristics of an individual (e.g., immune, metabolism, DNA damage response and hormone levels) and influence the key aspects of cell growth control and genome integrity.


The exposure to various epigenetic factors initially results in repairable DNA damage and upon continuous exposure to epigenetic factors and/or a genetic predisposition may lead to irreparable mutated cell and malignancy.[150] In this review, the etiology, clinical signs and symptoms, genes and the pathology involved and various tissue and blood markers of epithelial neoplasms were analyzed to arrive at an investigation protocol for disease-free individuals.

The analysis of the results of the study showed that though there are common etiological factors involved in the occurrence of various epithelial malignancies such as smoking, alcoholism and HPV, there are certain specific factors that influence the occurrence of malignancies in relation to a particular region or system involved. It was also observed that the usual clinical presentation of epithelial malignancies was a lump or ulceroproliferative growth. However, depending on the region or system involved, the clinical signs and symptoms vary from one another. A derivation of the specific etiological factors and clinical signs and symptoms of various epithelial neoplasms is tabulated [Table 5]. Usually, the signs and symptoms occur as a precancerous lesion initially and upon continuous insult, it progresses to malignancy. The genetic predisposition definitely influences the potential role of epigenetic factors in the development of cancer by inducing mutations that result in changes from normal mucosa to various grades of dysplasia to malignancy.[151]
Table 5: Specific etiological factors and clinical signs and symptoms of the epithelial neoplasms

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The lesions were able to be diagnosed clinically when it occurs in the oral cavity and cervical regions. However, lesions in other hidden areas were diagnosed using computed tomography, magnetic resonance imaging and endoscopic procedures. The authors have used histopathology as a gold standard method in diagnosing all the lesions and immunohistochemistry for diagnosing undifferentiated tumors as well as treatment planning. The authors have also used various markers in tissues and blood using different methods to diagnose the lesions. A derivation of the different tissue and blood markers used by various authors is tabulated [Table 6].
Table 6: Tissue and blood markers and their method of detection for various epithelial neoplasms

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With the help of the above derivations, the most commonly used blood markers were analyzed and tabulated to arrive at a prediction protocol [Table 7]. This investigation protocol involving various biomarkers is proposed in this review to predict genetic predisposition and/or chances of occurrence of malignancy in a disease-free individual. We propose that the markers suggested should be tested in every individual with a strong family history or persons with strong association of various epigenetic etiological factors without the disease. Though the limitations of our proposal will be cost factor and lack of confirmatory evidence, this is the first kind of proposal given here to predict genetic predisposition in a disease-free individual.
Table 7: Proposed investigation protocol

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   Conclusion Top


This review summarizes the different aspects of the epithelial neoplasm of various systems of our body based on the literature published. It is clear that cancer is an urgent global challenge and needs a definite measure to scale up prevention, early detection and diagnosis, treatment and care services. The analysis of various articles reveals the basic pathology, its genetic involvement, etiology, clinical symptoms and various diagnostic modalities of the epithelial neoplasm of the body, which are essential for any individual who deals with diagnosis or treatment or research in the field of oncology. Thus, the markers identified following the analysis of scientific facts behind a cancer may be helpful in predicting the genetic predisposition in a disease-free individual. It should be studied in a large scale either system wise or organ specific wise in future to confirm its specificity and sensitivity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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