Journal of Oral and Maxillofacial Pathology

: 2020  |  Volume : 24  |  Issue : 2  |  Page : 293--307

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

J Gowthami, N Gururaj, V Mahalakshmi, R Sathya, TR Sabarinath, Daffney Mano Doss 
 Department of Oral and Maxillofacial Pathology and Microbiology, CSI College of Dental Sciences and Research, Madurai, Tamil Nadu, India

Correspondence Address:
N Gururaj
Department of Oral and Maxillofacial Pathology and Microbiology, CSI College of Dental Sciences and Research, Madurai, Tamil Nadu


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.

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 Dec 1 ];24:293-307
Available from:

Full Text


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

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}

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}

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}{Table 3}{Table 4}

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.


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]


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]

Unmodifiable intrinsic risk which refers to inevitable spontaneous mutations (inherited) that arise as a result of DNA replicationNonintrinsic risk which refers to:

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; andEndogenous 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}

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}

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}


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


Conflicts of interest

There are no conflicts of interest.


1Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer 2011;2:466-74.
2Nagai H, Kim YH. Cancer prevention from the perspective of global cancer burden patterns. J Thorac Dis 2017;9:448-51.
3Hamdi Y, Boujemaa M, Ben Rekaya M, Ben Hamda C, Mighri N, El Benna H, et al. Family specific genetic predisposition to breast cancer: Results from Tunisian whole exome sequenced breast cancer cases. J Transl Med 2018;16:158.
4Wu S, Zhu W, Thompson P, Hannun YA. Evaluating intrinsic and non-intrinsic cancer risk factors. Nat Commun 2018;9:3490.
5Bruinooge SS. American Society of Clinical Oncology policy statement update: Genetic testing for cancer susceptibility. J Clin Oncol. 2003;21:2397-406.
6Zeybek A, Erdoǧan A, Gülkesen KH, Ergin M, Sarper A, Dertsiz L, et al. Significance of tumor length as prognostic factor for esophageal cancer. Int Surg 2013;98:234-40.
7Zappa C, Mousa SA. Non-small cell lung cancer: Current treatment and future advances. Transl Lung Cancer Res 2016;5:288-300.
8ACOG. PB179-Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol 2017;130:1-16.
9Allain DC. Genetic counseling and testing for common hereditary breast cancer syndromes: A paper from the 2007 William Beaumont hospital symposium on molecular pathology. J Mol Diagn 2008;10:383-95.
10Moosavi A, Ardekani AM. Role of epigenetics in biology and human diseases. Iran Biomed J 2016;20:246-58.
11Saleh K, Eid R, Haddad FG, Khalife-Saleh N, Kourie HR. New developments in the management of head and neck cancer-impact of pembrolizumab. Ther Clin Risk Manag 2018;14:295-303.
12Joshi P, Dutta S, Chaturvedi P, Nair S. Head and neck cancers in developing countries. Rambam Maimonides Med J 2014;5:e0009. Published 2014 Apr 28.
13Shaw R, Beasley N. Aetiology and risk factors for head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol 2016;130:S9-12.
14Perdomo S, Martin Roa G, Brennan P, Forman D, Sierra MS. Head and neck cancer burden and preventive measures in Central and South America. Cancer Epidemiol 2016;44 Suppl 1:S43-S52.
15Kumar M, Nanavati R, Modi TG, Dobariya C. Oral cancer: Etiology and risk factors: A review. J Cancer Res Ther 2016;12:458-63.
16Macfarlane TV, Wirth T, Ranasinghe S, Ah-See KW, Renny N, Hurman D. Head and neck cancer pain: Systematic review of prevalence and associated factors. J Oral Maxillofac Res 2012;3:e1.
17Shakeel MK, Daniel MJ, Srinivasan SV, Koliyan R, Kumar JV. Comparative analysis of detecting cervical lymph node metastasis with fine needle aspiration cytology. J Nat Sci Biol Med 2015;6(Suppl 1):S7-S9.
18De Rosa M, Pace U, Rega D, Costabile V, Duraturo F, Izzo P, et al. Genetics, diagnosis and management of colorectal cancer (Review). Oncol Rep 2015;34:1087-96.
19Kuipers EJ, Grady WM, Lieberman D, et al. Colorectal cancer. Nat Rev Dis Primers 2015;1:15065. Published 2015 Nov 5.
20Basini J, Rayadurgam S, Dakshinamurthy S. An overview of colorectal cancer: Implication of two medicinal plants in their treatment. Asian J Pharmaceutical and Clin Res 2019;12:47-52.
21Buechler SA, Gökmen-polar Y, Badve SS. EarlyR. A robust gene expression signature for predicting outcomes of estrogen receptor e positive breast cancer. Clin Breast Cancer 2019;19:17-26.e8.
22Ye Z, Wang C, Wan S, Mu Z, Zhang Z, Abu-Khalaf MM, et al. Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA. Eur J Cancer 2019;106:133-43.
23Mansfield CM. A review of the etiology of breast cancer. J Natl Med Assoc 1993;85:217-21.
24Ataollahi MR, Sharifi J, Paknahad MR, Paknahad A. Breast cancer and associated factors: A review. J Med Life 2015;8:6-11.
25Chen W, Zhang J, Huang L, Chen L, Zhou Y, Tang D, et al. Detection of HER2-positive circulating tumor cells using the liquid biopsy system in breast cancer. Clin Breast Cancer 2019;19:e239-46.
26Mahdavifar N, Towhidi F, Makhsosi BR, Pakzad R, Moini A, Ahmadi A, et al. Incidence and mortality of nasopharynx cancer and its relationship with human development index in the world in 2012. World J Oncol 2016;7:109-18.
27Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World J Hepatol 2015;7:2648-63.
28Badvie S. Hepatocellular carcinoma. Postgrad Med J 2000;76:4-11.
29Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient Prognosis. Gastroenterology 2017;152:745-761.
30Edmondson AJ, Birtwistle JC, Catto JW, Twiddy M. The patients' experience of a bladder cancer diagnosis: A systematic review of the qualitative evidence. J Cancer Surviv 2017;11:453-61.
31Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP. Superficial bladder cancer: An update on etiology, molecular development, classification, and natural history. Rev Urol 2008;10:31-43.
32Barbosa AL, Vermeulen SH, Aben KK, Grotenhuis AJ, Vrieling A, Kiemeney LA. Smoking intensity and bladder cancer aggressiveness at diagnosis. PLoS One 2018;13:e0194039.
33Kitamura H, Tsukamoto T. Early bladder cancer: Concept, diagnosis, and management. Int J Clin Oncol 2006;11:28-37.
34Metts MC, Metts JC, Milito SJ, Thomas CR Jr. Bladder cancer: A review of diagnosis and management. J Natl Med Assoc 2000;92:285-94.
35Oeyen E, Hoekx L, De Wachter S, Baldewijns M, Ameye F, Mertens I. Bladder cancer diagnosis and follow-up: The current status and possible role of extracellular vesicles. Int J Mol Sci 2019;20:821. Published 2019 Feb 14.
36Shephard EA, Stapley S, Neal RD, Rose P, Walter FM, Hamilton WT. Clinical features of bladder cancer in primary care. Br J Gen Pract 2012;62:e598-604.
37Leiting JL, Grotz TE. Advancements and challenges in treating advanced gastric cancer in the West. World J Gastrointest Oncol 2019;11:652-64.
38Kaur S, Baine MJ, Jain M, Sasson AR, Batra SK. Early diagnosis of pancreatic cancer: Challenges and new developments. Biomark Med. 2012;6:597-612.
39McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG, McCain RS. Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2018;24:4846-61.
40Kaur S, Baine MJ, Jain M, Sasson AR, Batra SK. Early diagnosis of pancreatic cancer: Challenges and new developments. Biomark Med 2012;6:597-612.
41Guntur D, Simadibrata M. Pancreatic cancer: Review of etiology, clinical features, diagnostic procedures, treatment and mesothelin role. Indonesian J Gastroenterology, Hepatology, and Digestive Endoscopy 2011;12:44-49.
42Agarwal B, Correa AM, Ho L. Survival in pancreatic carcinoma based on tumor size. Pancreas 2008;36:e15-e20.
43Moscicki AB, Ellenberg JH, Vermund SH, Holland CA, Darragh T, Crowley-Nowick PA, et al. Prevalence of and risks for cervical human papillomavirus infection and squamous intraepithelial lesions in adolescent girls: Impact of infection with human immunodeficiency virus. Arch Pediatr Adolesc Med 2000;154:127-34.
44Ramesh N, Anjana A, Kusum N, Kiran A, Ashok A, Somdutt S. Overview of benign and malignant tumours of female genital tract. J App Pharm Sci 2013;3:140-9.
45Buza N, Hui P. Immunohistochemistry in gynecologic pathology: An example-based practical update. Arch Pathol Lab Med 2017;141:1052-71.
46Cline JM. Neoplasms of the reproductive tract: The role of hormone exposure. ILAR J 2004;45:179-88.
47Wentzensen N, Vinokurova S, von Knebel Doeberitz M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res 2004;64:3878-84.
48Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: A review. Cancer Biol Med 2017;14:9-32.
49Farhood B, Geraily G, Alizadeh A. Incidence and mortality of various cancers in Iran and compare to other countries: A review article. Iran J Public Health 2018;47:309-16.
50Bray F, Lortet-Tieulent J, Ferlay J, Forman D, Auvinen A. Prostate cancer incidence and mortality trends in 37 European countries: An overview. Eur J Cancer 2010;46:3040-52.
51Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: A review. Environ Health Perspect 2003;111:1037-54.
52Weiderpass E, Labrèche F. Malignant tumors of the female reproductive system. Saf Health Work 2012;3:166-80.
53Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: Epidemiology, prevention, classification, and treatment. Cancer Manag Res 2018;10:239-48.
54Yusefi AR, Bagheri Lankarani K, Bastani P, Radinmanesh M, Kavosi Z. Risk factors for gastric cancer: A systematic review Asian. Pac J Cancer Prev 2018;19:591-603.
55Gupta AK, Bharadwaj M, Mehrotra R. Skin cancer concerns in people of color: Risk factors and prevention. Asian Pac J Cancer Prev 2016;17:5257-64. Published 2016 Dec 1.
56Gloster HM Jr, Neal K. Skin cancer in skin of color. J Am Acad Dermatol 2006;55:741-64.
57Bax MJ, Johnson TM, Harms PW, Schwartz JL, Zhao L, Fullen DR, et al. Detection of Occult Invasion in Melanoma In situ. JAMA Dermatol 2016;152:1201-8.
58Rastrelli M, Tropea S, Rossi CR, Alaibac M. Melanoma: Epidemiology, risk factors, pathogenesis, diagnosis and classification.In vivo 2014;28:1005-11.
59Domingues B, Lopes JM, Soares P, Pópulo H. Melanoma treatment in review. Immunotargets Ther 2018;7:35-49. Published 2018 Jun 7.
60Curiel-Lewandrowski C, Chen SC, Swetter SM; Melanoma Prevention Working Group-Pigmented Skin Lesion Sub-Committee. Screening and prevention measures for melanoma: Is there a survival advantage?. Curr Oncol Rep 2012;14:458-67.
61Cooley ME. Symptoms in adults with lung cancer. A systematic research review. J Pain Symptom Manage 2000;19:137-53.
62Holgate ST, Holloway JW. Is big beautiful? The continuing story of ADAM33 and asthma. Thorax 2005;60:263-4.
63Ganie F, Hussain S, Lone H, Wani ML, Wani S. Carcinoma lung: Clinical presentation, diagnosis, and its surgical management. J Assoc Chest Physicians 2013;1:38.
64Kasparian NA, McLoone JK, Meiser B. Skin cancer-related prevention and screening behaviors: A review of the literature. J Behav Med 2009;32:406-28.
65Latimer KM, Mott TF. Lung cancer: Diagnosis, treatment principles, and screening. Am Fam Physician 2015;91:250-6.
66Tvrda E, Agarwal A, Alkuhaimi N. Male reproductive cancers and infertility: A mutual relationship. Int J Mol Sci 2015;16:7230-60.
67John R, Giudicessi BA, Michael J, Ackerman. 2013. NIH public access. Bone 2008;23:1-7.
68Nguyen QT, Lee EJ, Huang MG, Park YI, Khullar A, Plodkowski RA. Diagnosis and treatment of patients with thyroid cancer. Am Health Drug Benefits 2015;8:30-40.
69Schneider DF, Chen H. New developments in the diagnosis and treatment of thyroid cancer. CA Cancer J Clin 2013;63:374-94.
70Soubra A, Risk MC. Diagnostics techniques in nonmuscle invasive bladder cancer. Indian J Urol 2015;31:283-8.
71Xiao X, Hu R, Deng FM, Shen SS, Yang XJ, Wu CL. Practical Applications of Immunohistochemistry in the Diagnosis of Genitourinary Tumors. Arch Pathol Lab Med 2017;141:1181-94.
72Koyuncuer A. Immunohistochemical expression of p63, p53 in urinary bladder carcinoma. Indian J Pathol Microbiol 2013;56:10-5.
73Weyerer V, Schneckenpointner R, Filbeck T, Burger M, Wild PJ, Fine SW, et al. Journal of cancer immunohistochemical and molecular characterizations in urothelial carcinoma of bladder in patients less than 45 years. J Cancer 2017;8:323-31. Published 2017 Feb 5.
74Schmitz-Dräger BJ, Droller M, Lokeshwar VB, Lotan Y, Hudson MA, van Rhijn BW, et al. Molecular markers for bladder cancer screening, early diagnosis, and surveillance: The WHO/ICUD consensus. Urol Int 2015;94:1-24.
75Inamura K. Bladder cancer: New insights into its molecular pathology. Cancers (Basel) 2018;10:100. Published 2018 Apr 1.
76Grossman HB, Messing E, Soloway M, Tomera K, Katz G, Berger Y, et al. Detection of bladder cancer using a point-of-care proteomic assay. JAMA 2005;293:810-6.
77Hou L, Tu J, Cheng F, Yang H, Yu F, Wang M, et al. Long noncoding RNA ROR promotes breast cancer by regulating the TGF-β pathway. Cancer Cell Int 2018;18:142.
78Myp C, Sym H, Thambiah M, Dw S, Jc C, Qs L, et al. Breast cancer: Current research immediate breast reconstruction does not delay adjuvant chemotherapy nor affect. Clin Outcome 2017;2:1-9.
79Sporikova Z, Koudelakova V, Trojanec R, Hajduch M. Genetic markers in triple-negative breast cancer. Clin Breast Cancer 2018;18:e841-50.
80Dong X, Men X, Zhang W, Lei P. Advances in tumor markers of ovarian cancer for early diagnosis. Indian J Cancer 2014;51 Suppl 3:e72-6.
81Prat J, Mutch DG. Pathology of cancers of the female genital tract including molecular pathology. Int J Gynaecol Obstet 2018;143 Suppl 2:93-108.
82Wang TL, Davidson B, Buckhaults PJ, Huang CS, Poul G. Molecular genetic markers in female reproductive cancers. J Oncol 2010;2010:307460.
83Rein BJ, Gupta S, Dada R, Safi J, Michener C, Agarwal A. Potential markers for detection and monitoring of ovarian cancer. J Oncol 2011;2011:475983.
84Soyano AE, Baldeo C, Kasi PM. Case report BRCA mutation and its association with colorectal cancer. Clin Colorectal Cancer 2018;17:e647-50.
85Kanik P, Gajjar K and Ghosh N. Immunohistochemical localization of KRAS and BRAF and its clinical utility in patients with colorectal cancer. Colorec Cancer 2018;4:04.
86Major AG, Pitty LP, Farah CS. Cancer stem cell markers in head and neck squamous cell carcinoma. Stem Cells Int. 2013;2013:319489.
87Mehrotra R, Yadav S. Oral squamous cell carcinoma: Etiology, pathogenesis and prognostic value of genomic alterations. Indian J Cancer 2006;43:60-6.
88Hoffmann F, Umbreit C, Krüger T, Pelzel D, Ernst G, Kniemeyer O, et al. Identification of proteomic markers in head and neck cancer using MALDI-MS imaging, LC-MS/MS, and immunohistochemistry. Proteomics Clin Appl 2019;13:e1700173.
89Suh Y, Amelio I, Guerrero Urbano T, Tavassoli M. Clinical update on cancer: Molecular oncology of head and neck cancer. Cell Death Dis 2014;5:e1018.
90Jou A, Hess J. Epidemiology and molecular biology of head and neck cancer. Oncol Res Treat 2017;40:328-32.
91Patil DB, Tekale PD, Patil HA, Padgavankar PH. Emerging applications of immunohistochemistry in head and neck pathology. J Dent Allied Sci 2016;5:89-94.
92Owusu-Afriyie O, Owiredu WK, Owusu-Danquah K, Larsen-Reindorf R, Donkor P, Acheampong E, et al. Expression of immunohistochemical markers in non-oropharyngeal head and neck squamous cell carcinoma in Ghana [published correction appears in PLoS One 2018;13:e0209696]. PLoS One 2018;13:e0202790. Published 2018 Aug 23.
93Yi CH, Jim Zhai Q, Wang BY. Updates on immunohistochemical and molecular markers in selected head and neck diagnostic problems. Arch Pathol Lab Med 2017;141:1214-35.
94Ni Y. What is the purpose of launching the World Journal of Methodology? World J Methodol 2011;1:1-3.
95Rajguru JP, Mouneshkumar CD, Radhakrishnan IC, Negi BS, Maya D, Hajibabaei S, et al. Tumor markers in oral cancer: A review. J Family Med Prim Care 2020;9:492-6. Published 2020 Feb 28.
96Daher S, Massarwa M, Benson AA, Khoury T. Current and future treatment of hepatocellular carcinoma: An updated comprehensive review. J Clin Transl Hepatol 2018;6:69-78.
97Pietrantonio F, De Braud F, Da Prat V, Perrone F, Pierotti MA, Gariboldi M, et al. A review on biomarkers for prediction of treatment outcome in gastric cancer. Anticancer Res 2013;33:1257-66.
98McCormick Matthews LH, Noble F, Tod J, Jaynes E, Harris S, Primrose JN, et al. Systematic review and meta-analysis of immunohistochemical prognostic biomarkers in resected oesophageal adenocarcinoma. Br J Cancer 2015;113:107-18.
99Wang C, Wang J, Chen Z, Gao Y, He J. Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: A systematic review. Chin J Cancer 2017;36:65.
100Tan C, Qian X, Guan Z, Yang B, Ge Y, Wang F, et al. Potential biomarkers for esophageal cancer. Springerplus 2016;5:467.
101Visser E, Franken IA, Brosens LA, Ruurda JP, van Hillegersberg R. Prognostic gene expression profiling in esophageal cancer: A systematic review. Oncotarget 2017;8:5566-77.
102Wang Y, Cao Z, Wang L, Liu S, Cai J. Downregulation of microRNA-142-3p and its tumor suppressor role in gastric cancer. Oncol Lett 2018;15:8172-80.
103Duffy MJ, Sturgeon C, Lamerz R, Haglund C, Holubec VL, Klapdor R, et al. Tumor markers in pancreatic cancer: A European Group on Tumor Markers (EGTM) status report. Ann Oncol 2010;21:441-7.
104Goonesekere NC, Wang X, Ludwig L, Guda C. A meta analysis of pancreatic microarray datasets yields new targets as cancer genes and biomarkers. PLoS One 2014;9:e93046.
105Ferrone CR, Finkelstein DM, Thayer SP, Muzikansky A, Fernandez-delCastillo C, Warshaw AL. Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J Clin Oncol 2006;24:2897-902.
106Smith RA, Tang J, Tudur-Smith C, Neoptolemos JP, Ghaneh P. Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer 2011;104:1440-51.
107Loosen SH, Neumann UP, Trautwein C, Roderburg C, Luedde T. Current and future biomarkers for pancreatic adenocarcinoma. Tumour Biol 2017;39:1010428317692231.
108Hamada S, Shimosegawa T. Biomarkers of pancreatic cancer. Pancreatology 2011;11 Suppl 2:14-9.
109Malati T. Tumour markers: An overview. Indian J Clin Biochem 2007;22:17-31.
110Soumya D. A Glimpse on melanoma-risk factors and treatment. J Cancer Sci Ther 2011;3:1-6.
111Weinstein D, Leininger J, Hamby C, Safai B. Diagnostic and prognostic biomarkers in melanoma. J Clin Aesthet Dermatol 2014;7:13-24.
112Sonthalia S, Agrawal M, Sehgal VN. Topical ciclopirox olamine 1%: revisiting a unique antifungal. Indian Dermatol Online J 2019;10:481-5.
113Lim SY, Lee JH, Diefenbach RJ, Kefford RF, Rizos H. Liquid biomarkers in melanoma: Detection and discovery. Mol Cancer 2018;17:8.
114He T, Wu J, Chen Y, Zhang J. TP 53 polymorphisms and melanoma: A meta-analysis. J Cancer Res Ther 2015;11:409-14.
115Inamura K. Lung cancer: Understanding its molecular pathology and the 2015 WHO classification. Front Oncol 2017;7:193.
116Cheng L, Alexander RE, Maclennan GT, Cummings OW, Montironi R, Lopez-Beltran A, et al. Molecular pathology of lung cancer: Key to personalized medicine. Mod Pathol 2012;25:347-69.
117Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243-60.
118Thapa J. The molecular pathology of thyroid neoplasms. J Pathol Nepal 2014;4:580-3.
119Abdullah MI, Junit SM, Ng KL, Jayapalan JJ, Karikalan B, Hashim OH. Papillary thyroid cancer: Genetic alterations and molecular biomarker investigations. Int J Med Sci 2019;16:450-60.
120Nosé V. Familial thyroid cancer: A review. Mod Pathol 2011;24:S19-33.
121Li X, He J, Zhou M, Cao Y, Jin Y, Zou Q. Identification and validation of core genes involved in the development of papillary thyroid carcinoma via bioinformatics analysis. Int J Genomics. 2019;2019:5894926. Published 2019 Sep 8.
122Nagirnaja L, Aston KI, Conrad DF. Genetic intersection of male infertility and cancer. Fertil Steril 2018;109:20-6.
123Achermann JC, Ozisik G, Meeks JJ, Larry Jameson J. Perspective: Genetic causes of human reproductive disease. J Clin Endocrinol Metab 2002;87:2447-54.
124Nagirnaja L, Aston KI, Conrad DF. Genetic intersection of male infertility and cancer. Fertil Steril 2018;109:20-6.
125Achermann JC, Ozisik G, Meeks JJ, Larry Jameson J. Perspective: Genetic causes of human reproductive disease. J Clin Endocrinol Metab 2002;87:2447-54.
126Wei J, Wang Z. Establishment of a predictive model for short-term efficacy of transcatheter arterial chemoembolization treatment in hepatocellular carcinoma and its clinical application. J Cancer Res Ther 2019;15:941-6.
127Pall M, Iqbal J, Singh SK, Rana SV. CA 19-9 as a serum marker in urothelial carcinoma. Urol Ann 2012;4:98-101.
128Bedeir A, Krasinskas AM. Molecular diagnostics of colorectal cancer. Arch Pathol Lab Med 2011;135:578-87.
129Pectasides D, Bafaloucos D, Antoniou F, Gogou L, Economides N, Varthalitis J, et al. TPA, TATI, CEA, AFP, beta-HCG, PSA, SCC, and CA 19-9 for monitoring transitional cell carcinoma of the bladder. Am J Clin Oncol 1996;19:271-7.
130Zhang X, Ran W, Wu J, Li H, Liu H, Wang L, et al. Deficient mismatch repair and RAS mutation in colorectal carcinoma patients: A retrospective study in Eastern China. PeerJ 2018;6:e4341.
131Gao XH, Yu GY, Gong HF, Liu LJ, Xu Y, Hao LQ, et al. Differences of protein expression profiles, KRAS and BRAF mutation, and prognosis in right-sided colon, left-sided colon and rectal cancer. Sci Rep 2017;7:7882.
132Huang YL, Wu JR, Fang M, Zhao HL, Liu ZM, Ye J, et al. The role of ERCC1 and AFP gene polymorphism in hepatocellular carcinoma. Medicine (Baltimore) 2019;98:e15090.
133Garinet S, Laurent-Puig P, Blons H, Oudart JB. Current and future molecular testing in NSCLC, what can we expect from new sequencing technologies?. J Clin Med 2018;7:144. Published 2018 Jun 9.
134Dolejsova O, Kucera R, Fuchsova R, Topolcan O, Svobodova H. The ability of prostate health index (PHI) to predict Gleason score in patients with prostate cancer and discriminate patients between Gleason score 6 and Gleason score higher than 6 — A study on 320 patients after radical prostatectomy. Technol Cancer Res Treat. 2018;17:1533033818787377.
135Ziske C, Schlie C, Gorschlüter M, Glasmacher A, Mey U, Strehl J, et al. Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine. Br J Cancer 2003;89:1413-17.
136Zhang J, Quadri S, Wolfgang CL, Zheng L. New development of biomarkers for gastrointestinal cancers: From neoplastic cells to tumor microenvironment. Biomedicines 2018;6:87. Published 2018 Aug 13.
137Mayer-Zitarosa A. Clinical effectiveness of cancer screening biomarker tests offered as self-pay health service: A systematic review. Eur J Public Health 2016;26:498-505.
138Venyo AK, Herring D, Greenwood H, Maloney DJ. The expression of beta human chorionic gonadotrophin (β-HCG) in human urothelial carcinoma. Pan Afr Med J 2010;7:20.
139Rapisuwon S, Vietsch EE, Wellstein A. Circulating biomarkers to monitor cancer progression and treatment. Comput Struct Biotechnol J 2016;14:211-22. Published 2016 Jun 1.
140Hsiao Y, Chu LJ, Chen J, Yeh T, Yu J. Expert review of proteomics proteomic profiling of the cancer cell secretome: Informing clinical research. Expert Rev Proteomics 2017;14:737-56.
141Sauter ER. Reliable biomarkers to identify new and recurrent cancer. Eur J Breast Health 2017;13:162-7.
142Bandu R, Oh JW, Kim KP. Mass spectrometry-based proteome profiling of extracellular vesicles and their roles in cancer biology. Exp Mol Med 2019;51:1-0.
143Sallam RM. Proteomics in cancer biomarkers discovery: Challenges and applications. Dis Markers 2015;2015:321370.
144Hanash S, Schliekelman M. Proteomic profiling of the tumor microenvironment: Recent insights and the search for biomarkers. Genome Med 2014;6:12.
145Lee CH, Im EJ, Moon PG, Baek MC. Discovery of a diagnostic biomarker for colon cancer through proteomic profiling of small extracellular vesicles. BMC Cancer 2018;18:1058.
146Hayes B, Murphy C, Crawley A, O'Kennedy R. Developments in point-of-care diagnostic technology for cancer detection. Diagnostics (Basel) 2018;8:39. Published 2018 Jun 2.
147Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, et al. Exosomes: Novel biomarkers for clinical diagnosis. Scientific World J 2015;2015:657086.
148Maruvada P, Wang W, Wagner PD, Srivastava S. Biomarkers in molecular medicine: Cancer detection and diagnosis. Biotechniques 2005;Suppl: 9-15.
149Eftimie R, Hassanein E. Improving cancer detection through combinations of cancer and immune biomarkers: A modelling approach. J Transl Med 2018;16:73.
150Sadikovic B, Al-Romaih K, Squire JA, Zielenska M. Cause and consequences of genetic and epigenetic alterations in human cancer. Curr Genomics 2008;9:394-408.
151Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2009;31:27-36.