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

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. Copyright:

INTRODUCTION

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.[23] 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.[567] 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.[57] 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.[89] 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

Flowchart for the systematic review

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

Database	Keyword and search method
PubMed	Epithelial neoplasm AND etiologic factors
	Epithelial neoplasm AND clinical feature
	Epithelial neoplasm AND genetic predisposition
	Epithelial neoplasm AND biomarkers
	Epithelial neoplasm AND blood markers
	Pathology AND genes involved
Embase	Head and neck cancer AND blood markers
	Lung cancer AND blood markers
	Breast cancer AND blood markers
	Colorectal cancer AND blood markers
	Cancer of female reproductive tract AND blood markers
	Cancer of male reproductive tract AND blood markers
	Thyroid cancer AND blood markers
	Pancreas cancer and blood markers
	Head and neck cancer AND tissue markers
	Lung cancer AND tissue markers
	Breast cancer AND tissue markers
	Colorectal cancer AND tissue markers
	Cancer of female reproductive tract AND tissue markers
	Caner of male reproductive tract AND tissue markers
	Thyroid cancer AND tissue markers
	Pancreas cancer and tissue markers
Cochrane	Head and neck cancer AND genetic predisposition
	Lung cancer AND genetic predisposition
	Breast cancer AND genetic predisposition
	Colorectal cancer AND genetic predisposition
	Cancer of female reproductive tract AND genetic predisposition
	Cancer of male reproductive tract AND genetic predisposition
	Thyroid cancer AND genetic predisposition
	Pancreas cancer and genetic predisposition

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 Tables 2–4. The collected data were independently analyzed by each author.

Table 2

Etiological factors and clinical signs and symptoms

Criteria	Head-and-neck cancer	Colorectal cancer	Breast cancer	Liver cancer	Bladder cancer	Pancreatic cancer	Cancer of female reproductive tract: cervical, uterine, ovarian	Cancer of male reproductive organ: prostrate testis	Lung cancer	Thyroid cancer	Gatrointestinal cancer	Skin cancer
Author details	Saleh K, Joshi P, Dutta, Shaw R, Perdomo S, Macfarlane T V, Omar EA	Rosa M De, Boelens PG, Granadosro, Mero JJ	Buechler SA, Ye Z, Wang C, Mansfield CM Sharifi J, Chen W,	Mohammadian M, Waller LP, Badvie S. Sia D,	Edmondson AJ, Pasin E, Barbosa LA, Metts MC, Soubra A, Shephard EA	Malhotra L, Be C, Earl F, Mcguigan A, Factors R, Darmawan G	Moscicki A, Ramesh N, Cline JM. Wentzensen N, Hedayatizadeh- omran A, Herbst L. markers, Flake GP Weiderpass E	Tvrda E, John R.Giudicessi	Factors R, Cooley ME. Holgate ST, Ganie F Latimer KM,	Nguyen QT,	Management C. Yusefi AR,	Factors R, Patients FOR. Bax MJ, Johnson TM, Rastrelli M, Das P Melanoma C, Cancer S, Found B
Etiological factors	HPV Fungal infection Sharp teeth Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Red meat consumption Processed food NSAIDS Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Hormonal factors Young-age menarche Regular/irregular menstrual cycle Older age menopause Oral contraceptives Family history, smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Chronic hepatitis with advanced fibrosis/cirrhosis Hereditary hemochromatosis Alpha-1 antitrypsin deficiency Porphyria’s Fatty liver disease Wilson’s disease Glycogen storage disease Tyrosinemia type I Hereditary telangiectasia Hypercitruelimia Aflatoxin exposure Polyvinyl chloride Carbon chloride Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruits and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Cooking in fumed wood Industrial carcinogen: aromatic amines, azodyes Gasoline exhaust Methenamine vapor Drugs: cyclophosphamide, chloromethane, phenacetin, nitrosamines Chlorinated water Hair dyes Saccharine’s HSV infection Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Exposure to pollutants Chronic pancreatitis disease Gall stones Pylori Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	HPV HSV Family history, smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Selenium Androgens Vasectomy Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Air pollution Radon gas Asbestos Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	X-rays Radioactive iodine Hypo- and hyper-thyroidism Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	HPV Pylori HPV 16 and 18 Acid and bile reflux Increase in salt intake Polyaromatic hydrocarbons Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D	Serious blistering sun burns UV radiation Family history Smoking, diabetes, alcohol consumption, obesity, decreased physical activity, decrease in fruit and vegetable consumption, decrease in the consumption of dairy products, decrease in the consumption of folate, fibers and Vitamin D
Clinical signs and symptoms	Red/whitish patch Ulcero proliferative growth, Lump/mass without pain Hoarseness Frequent epistaxis Difficulty in breathing Double vision Difficulty in chewing/swallowing	Polyp- inner lining of the colon/rectum Bleeding from the rectum Blood in stool after the bowel movement Cramping in the lower abdomen Urge for bowel emptying Constipation and diarrhea last for few days Decrease in appetite Weight loss	Lump in the breast Painful Nipple Nipple discharge: blood discharge	Hepatitis/cirrhosis Large tumors may cause abdominal pain Malaise Weight loss Fatigue Fullness Jaundice Paraneoplastic syndrome Hypercalcemia Hormonal imbalance GIT/esophageal bleeding	Hematuria Changes in the bladder habit Urinate more often Pain during urination Bladder fullness Weak urine stream Unable to urinate Lower back ache Swelling in the feet	Nausea Vomiting Bloating Steatorrhea Abdominal pain Weight loss Jaundice Ascites Gastrointestinal bleeding Hepatomegaly	Back pain Edema in the lower extremity Uterine bleeding Irregular postmenopausal bleeding Dysuria Bloating	Difficulty in urinating Prostrate hypertrophy Back pain Hemoptysis Gynecomastia	Fatigue Labored breathing Persistent cough Decreased appetite Hoarseness of voice Wheeze, Stridor pneumonia	Nodule single/multiple Dyspepsia Dyspnea Hoarseness Cervical lymphadenopathy	Nausea Vomiting Bleeding Ulcer Weight loss Steatorrhea Abdominal pain Bloating Dysphagia Dyspepsia	Irregularity of the mole Blurred/ragged edges Alteration in the pigmentation Increase in the size and shape of the mole Itching/tenderness of the mole Pain and Swelling of the lymph nodes
Diagnosis	Stage I	Stage I	Stage I	Stages II and III	Stage I	Stages III and IV	Stages I and II	Stages I and II	Stages I and II	Stages I and II	Stage I	Stages I and II

HPV: Human papillomavirus, HSV: Herpes simplex virus, NSAIDS: Nonsteroidal anti-inflammatory drugs, UV: Ultraviolet, Pylori: Helicobacter Pylori, GIT: Gastrointestinal tract

Table 4

Markers used by authors for various types of epithelial neoplasms

Author details	Markers	Type of specimen	Detection
Biaogeng et al.	CA 15-3 CEA	Serum	Breast cancer and its subtypes
Dorit laessig1 et al.	CA 15-3 CEA	Serum	Breast cancer and its subtypes
Alireza Abdullahi et al.	ER PR	Tissue (IHC)	Breast cancer and its subtypes
	P53
	HER 2
Valentina Guarneri et al.	HER 2	Tissue (IHC)	Breast cancer and its subtypes
Grazia Carpino et al.	HER 2	Tissue (IHC)	Breast cancer and its
	HER 1		subtypes
Seyedabbasmirmalek et al.	HER 2 P53 Hormone receptor	Tissue (IHC)	Breast cancer and its subtypes
Michael j. Duffy	CA 15-3	Serum	Breast cancer and its
	BR 27.29		subtypes
	CEA
	TPA
	TPS HER-2
Catherine e. Bond et al.	BRAF	Tissue	Colorectal cancer
Michael j. Duffy	CEA	Serum	Colorectal cancer
John h. Bond, MD	FOBT	Blood	Colorectal cancers
Alyssa M. Krasinski’s	EGFR	Blood	Colorectal cancers
	KRAS
	BRAF (genes)
	PIK3CA
Gadepalli et al.	EGFR	Blood	Colorectal cancers
Chan dihedral	EGFR	Blood	Colorectal cancer
Jincheng et al.	ALK AND its inhibitor	Blood	Lung
Gilda da concha santos	EGFR	Blood and tissues (IHC)	Lung
Fernando c. Santini et al.	PD1	Blood and tissues (IHC)	Lung
D.Ed. Meyers et al.	PD-1/PD-L1 AXSIS	Blood	Lung
Oliver Dorigo et al.	CA125	Blood	Ovarian
T van Gore et al.	HE4 CA 125	Blood	Ovarian
John o. Scourge et al.	OPN	Blood	Ovarian
Lalita a. Shaved et al.	OPN	Blood	Ovarian
J. L. Humphries et al.	CA19.9	Serum	Pancreas
Ewe karna et al.	IGFR I	Serum	Pancreas
	IGF
R.talar-wojnarowska et al.	VEGF	Serum	Pancreas
Leonard s. Marks et al.	PCA3	Blood	Prostrate
Dragan Iliac et al.	PSA	Blood	Prostrate
Ji-fan lin et al.	MICRO RNA	Blood	Bladder cancer
Weige tan et al.	MICRO RNA25	Blood	Gastric cancer
	P57
José marrugo et al.	Heat shock proteins	Blood	All cancers
Edward r. Sauter	Hormone receptor status	Tissue	All cancer
	CK
	HER2
	Ki67
	Oncotype Dx
	MammaPrint
Kiran Dahiya et al.	Chemokine receptor	Tissue/saliva	Head and cancer
	MMP
	HPV
	Interleukin MicroRNA
	MAGE
	Actin and myosin
Esam Ahmad Omar	ZEB1, ZEB2	Blood	Head and cancer
	KRAS
	PTEN
	P21
	miRNA
Saleh Daher et al.	miR-122	Blood	Liver cancer
	RASSF1A
	Histone-modifying genes
Daniela Sia et al.	KRAS	Tissue/blood	Liver cancer
	TP53
	EGFR
	BRAF
David Weinstein, md et al.	Melan-A, BUB1 and CD 63 RREB1 (6p25), MYB (6q23), Cep6 (Centromere	Tissue/blood	Melanoma
	6), CDKN2A (9p21), RREB1 (6p25), MYC (8q24)
Su yin lim et al.	BRAF	Tissue/blood	Melanoma
	CXCL3
	VEGF
Xiliangwang et al.	THCA	Blood	Thyroid cancer
	TSHR
	TTF
Buddhike Sri Harsha Indrasena	Thyroglobulin	Blood	Thyroid cancer

CA: Cancer antigen, CEA: Carcinoembryonic antigen, ER: Estrogen receptor, PR: Progesterone receptor, p53: Tumor suppressor, HER: Heregulin, TPA: Serum tissue polypeptide antigen, TPS: Tissue polypeptide-specific antigen, BRAF: Proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, FOBT: The fecal occult blood test, EGFR: Epidermal growth factor receptor, KRAS: Kirsten rat sarcoma viral oncogene homolog, PIK3CA: Phosphatidylinositol 3-kinase, ALK: Anaplastic lymphoma kinase, PDL1: Programmed death-ligand 1, HE4: Human epididymis protein 4, OPN: Osteopontin, IGFR: Insulin-like growth factor receptor, VGEF: Vascular endothelial growth factor, MMP: Matrix metalloproteinase, MAGE: Tumor-specific antigen, ZEB: Zinc finger E-box binding homeobox, PTEN: Phosphatase and tensin homolog, BUB: Mitotic checkpoint protein, MYC: Basic helix-loop-helix protein, THCA: Tetrahydrocannabinol acid, TSHR: Thyroid-stimulating hormone receptor, TTR: Transthyretin, CA 15-3: Cancer antigen 15-3, UV: Ultraviolet

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

Author details, etiological factors and clinical signs and symptoms of the various epithelial neoplasms are tabulated in Table 2.[1112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146147148149]

The genes and the pathology involved in the various epithelial neoplasms are tabulated in Table 3.[1112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146147148149]

Table 3

Genes and pathology involved in various epithelial neoplasms

Tumor	Author details	Pathology	Genes involved
Head-and-neck cancer	Major AG, Mehrotra R, Hoffmann F, Suh Y, Jou A, Patil DB, Owusu-afriyie O, Yi C, Dahiya K, Negi M	TP 53 Rb 17 LOH	P169pLOH
Colorectal cancer	Soyano AE, Kanik P	APC -5q21-22	P16
		Mismatch MSH 2, MSH3, MLH1	P15
		PMS 1	BUB 1
		MSH 6	Cyclin D1
			MMP
			E-cadherin
			CD44
Breast cancer	Hou L, Myp C, Sporikova Z	LOH at multi loci	Ki67
		BRCA1	MIB 1
		BRCA 2	Topoisomerase
		Estrogen receptor - positive	histone H3
		P53 mutation	TGF alpha, beta
		Heterozygosity ATM	EGF
		P53	P53
		cerbB2	Caspases
		BCL	surviving
			P21
			CD31,44, VGEF
			Brca1
Liver cancer	Daher S	Adenomatous hyperplasia	Aflatoxin B1
		Alpha-fetoprotein	P53
			Cyclin D
			KRAS
			Beta-catenin
Bladder cancer	Soubra A, Xiao X, Koyuncuer A,	Mutation - NAT2 gene	9- LOH
	Weyerer V, Ogawa O, Inamura K,	GSTM - detoxification	Cyclin D
	Ifeanyi OE	ERBB 2 Partial loss of chromosome 9	VGEF P53
		P16	RB
		P15	PDECGF
		P53
Pancreatic cancer	Duffy MJ, Goonesekere NCW,	BRCA2	KRAS
	Zapata M, Smith RA, Loosen SH,	P16	MYB
	Hamada S, Malati T	STK1	AKT2
		LKB1	AIB1
		Mutation of trypsinogen gene - 7q35	ERBB2
			P16
			P53
			DPC4
			BRCA2
			MKK4
			MAH 2
			MLH1
Gastrointestinal cancer	Pietrantonio F, Matthews LHM, Wang C, Tan C, Visser E, Wang	CAG gene mutation E-cadherin mutation	KRAS C-MET
	YI	LOH 1q3p, 5q, 6q, 7q, 9p, 17p	C-ERBB2
		P53	CYCLIN D
		AT CG mutation	APC
		Cyclin D	P53
		HST1	Cadherin and cantenin
		HST2
		EGFR	CD44 translocation
		Myc-polymorphism	P53
			APC
			FHIT
			CDKN2A
			CD95
			FAS
			EGFR
			C-ERBB2
			UPA
			KI67 RAB1
Skin cancer	Weinstein D, An I, Harman M, Lim SY, He T, Soumya D	Loss of function of melanocortin receptor1	CDK1 MC 1P
		Cdkn2a mutation	P53
		P16	MYC
		CDK 4
		CDKN2
		PTEN-1p, 6q, 7p, 11q
		P53
		Myc
		BRAF
Cancer of female reproductive tract: cervical, uterine, ovarian	Dong X, Prat J, Wang T Rein BJD	CIN 1,2,3,4	HPV
		Diploid/polypoid associated with HPV	FHIT
		c-myc	P53
		N-MYC	KRAS
		KRAS	MYC
		FHIT	LOH-3P
		CYT P141	PTEN
		C-ERBB2	BRCA
		PTEN	P16
		LOH 3P	Cyclin D1
			E-cadherin
			CD44
Cancer of male reproductive	Nagirnaja L, Achermann JC	P53 BCL2	LOSS of 8P21 NKX 3.1
organ: Prostrate testis		Mutation IN X chromosome 1P	10Q
		Iscero 12P	13Qrb
		Cyclin D	P53
Lung cancer	Inamura K Cheng L, Travis WD	Polymorphism of cytochrome p450 gene	P53 KRAS
		P 53 mutation	CDKN2a
		Point mutation-KRAS	P16
		FHIT (fragile histidine triad) 3p	LOH 3p
		14.2- preneoplastic lesion	FHIT
		Homozygous deletion and silencing methylation in CDK inhibitors p16ink
Thyroid cancer	Thapa J	MEN type 2A	TSH
	Abdullah MI, Nosé V	RET proto-oncogene	RAS
	Li X, He J	Mutation of PTC 1, 2, 3	LOH 3P PAX 8
			PTEN
			P53
			RET/PTC
			TRK
			BRAF
			MFT

TP 53: Tumor suppressor gene, LOH: Loss of heterozygosity, P16: Cyclin-dependent kinase inhibitor 2A, APC: Adenomatous polyposis coli, MSH: Mut S protein homolog, MLH-1: Mut L protein homolog 1, PMS 1: Protein homolog 1, BUB: Budding uninhibited by benzimidazole 1, MMP: Matrix metalloproteinases, P15: Multiple tumor suppressor gene, CD 44: Cell surface glycoprotein, cell-cell interactions, BRCA: Breast cancer gene, ATM: Ataxia-telangiectasia mutated, cerbB2: Receptor tyrosine-protein kinase erbB-2, BCL: B-cell lymphoma, ki67: Nuclear protein associated with cellular proliferation, MIB: E3 ubiquitin-protein ligase, TGF: Transforming growth factor, P21: Potent cyclin-dependent kinase inhibitor, CD 31: Platelet endothelial cell adhesion molecule, NAT: N-acetyltransferase, GSTM: Glutathione S-transferase Mu 1, KRAS: Kirsten rat sarcoma viral oncogene homolog, RB: Retinoblastoma, PDECGF: Thymidine phosphorylase, STK: Serine/threonine kinase family, LKB: Liver kinase B1, MYB: Myeloblastosis, AKT: Protein kinase B, AIB: Transcription factor ABA-inducible bHLH-TYPE, DPC4: Deleted in pancreatic cancer-4, MKK: Mitogen-activated protein kinase, MYC: Proto-oncogene BHLH transcription factor, HST: Human gene nomenclature, CDK: Cyclin-dependent kinase, CAG: Cytosine-adenine-guanine, C-MET: Tyrosine-protein kinase, CD 95: Apoptosis antigen 1, FAS: Cell surface death receptor, FHIT: Human accelerated region 10, UPA: Urokinase-type plasminogen activator-Ras-related in brain, BRAF: Raf murine sarcoma viral oncogene homolog B, PTEN: Phosphatase and tensin homolog, MEN: Multiple endocrine neoplasia type, RET: Rearranged during transfection, PAX: Paired box, TMFTRK: Tropomyosin receptor kinase A, MFT: phosphatidylethanolamine-binding protein

The biomarkers used by authors for the various epithelial neoplasms are shown in Table 4.[1112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146147148149]

DISCUSSION

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 replication

Nonintrinsic 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; and

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

Criteria	Head-and - neck cancer	Colorectal cancer	Breast cancer	Liver cancer	Bladder cancer	Pancreatic cancer	Cancer of female reproductive tract: cervical, uterine, ovarian	Cancer of male reproductive organ: prostrate testis	Lung cancer	Thyroid cancer	Gatrointestinal cancer	Skin cancer
Specific etiological factors	HPV Fungal infection Sharp teeth	Red meat consumption Processed food NSAIDS	Hormonal factors Young-age menarche Regular/irregular menstrual cycle Older-age menopause Oral contraceptives	Chronic hepatitis with advanced fibrosis/cirrhosis Hereditary hemochromatosis Alpha-1 antitrypsin deficiency Porphyria’s Fatty liver disease Wilson’s disease Glycogen storage disease Tyrosinemia type I Hereditary telangiectasia Hypercitruelimia Aflatoxin exposure Polyvinyl chloride Carbon chloride	Cooking in fumed wood Industrial carcinogen: aromatic amines, azodyes Gasoline exhaust Methenamine vapor Drugs: Cyclophosphamide, chloromethane, phenacetin, nitrosamines Chlorinated water Hair dyes Saccharine’s HSV infection	Exposure to pollutants Chronic pancreatitis disease Gall stones Pylori	HPV HSV	Selenium Androgens Vasectomy	Air pollution Radon gas Asbestos	X rays Radioactive iodine Hypo- and hyper- thyroidism	HPV Pylori HPV 16 and 18 Acid and bile reflux Increase in salt intake Polyaromatic hydrocarbons	Serious blistering sun burns UV radiation
Specific clinical signs and symptoms	Red/whitish patch Ulcero proliferative growth, Lump/mass without pain Hoarseness	Bleeding from the rectum Blood in stool after the bowel movement Cramping in the lower abdomen	Lump in the breast Painful nipple and discharge	Hepatitis/cirrhosis Large tumors may cause abdominal pain Malaise Weight loss	Hematuria Changes in the bladder habit Urinate more often Pain during urination	Nausea Vomiting Bloating Steatorrhea	Back pain Edema in the lower extremity	Difficulty in urinating Prostrate hypertrophy	Labored breathing Persistent cough Decreased appetite Hoarseness of voice Wheeze, stridor	Nodule (single/multiple) Dyspepsia Dyspnea	Nausea Vomiting Bleeding Ulcer Dysphagia Dyspepsia	Irregularity of the mole Blurred/ragged edges Alteration in the pigmentation
Diagnosis	Stage I	Stage I	Stage I	Stages II and III	Stage I	Stages III and IV	Stages I and II	Stages I and II	Stages I and II	Stages I and II	Stage I	Stages I and II

UV: Ultraviolet

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

Tumor	Tissue markers	Blood markers	Method of analysis
Head-and-neck cancer	KERATINS	AFP, CEA, pancreatic oncofetal antigen 2.	Immunoassay
	EMA	CA125, CA19-9, CA15-3	Immunohistochemistry, PCR
	TPA	Beta-human chorionic gonadotropin	ELISA
	Vimentin and desmin	calcitonin
	MMPS	Albumin
	BMA
	P16
	P53
	MAC
	Interleukin-1ALPHA
	Endothelins
	CD 44
Colorectal cancer	Microsatellite instability: MMR genes,	Microsatellite instability: MMR genes,	PCR
	MSH2, MLH1, MSH6 and PMS2	MSH2, MLH1, MSH6 and PMS2	ELISA
	KRAS, EGFR, NRAS	IGFBP2	PCR
	BRAF, PTEN, PIK3CA, ERCC-1	Telomerase	ELISA
	S100A2 protein	PKM2	PCR
		Ezrin, P53, cyclooxygenase-2, 18q, LOH and TNIK	IHC PCR, IHC, ELISA
			IHC
Breast cancer	ER, PR	CA 15.3	Immunoassay
	HER2	CA 27.29	Immunohistochemistry
	CA 15-3	CA125
	Oncotype DX	CEA
	MammaPrint	Circulating tumor cells
	up A/PAI-1	Human epididymis protein 4
	Ki67	Cyclin E
		Cathepsin D
		up A
		Leptin
		PAI-1
		P53
		CA 15-3
Liver cancer	GPC3	AFP	Immunoassay
	GPC3+heat shock protein	CEA	Immunohistochemistry
	Ki-67	Ferritin	GENETIC MARKER
	MIB-1	α1-antitrypsin	PCR, ELISA
	E-cadherin	α1-acid glycoprotein
	β-catenin	Osteopontin
	Plasma glutamate carboxy-peptidase,	Aldolase A
	phospholipases A2 G13 and G7 and other	CK18,
	cDNA microarray-derived encoded proteins	CK19,
	Melanoma antigen gene 1, 3; synovial	TPA,
	sarcoma on X chromosome 1, 2, 4, 5;	TPS
	sarcoplasmic calcium-binding protein 1;	Circulating free squamous cell carcinoma antigen-IgM complexes
Bladder cancer	CKs 19	HCE BETA	Urine markers - immunoassay
	Survivin	CEA	immunohistochemistry
	Telomerase	NMP22
	BCLA 4	BTA Stat 2
	Microsatellite	BTA Trak
	FGFR 3	NMP22
	Hyaluronic acid
	Hyaluronidase
Pancreatic cancer	Human equilibrative nucleoside transporter	CA19-9	Immunoassay
	1	CEA	Immunohistochemistry
	MICRO RNA	MUC-4
	P16	MUC-1
	P53	CEACAM1
	TELOMERASE	MIC1
	S100 P	CTC
Stomach cancer	CKs	CA19-9	Immunoassay
	CYFRA 21.1, TPA, TPS	CEA	Immunohistochemistry
	β Subunit of HCG	CA72-4
Esophageal cancer	HER2	BRAF	Immunohistochemistry,
	PDL1	CA19-9	PCR
		CEA	ELISA
Melanoma	MT DNA	S-100	Immunoassay
		BRAF	Immunohistochemistry
Cancer of female	M-CSF	SCC	IMMUNOASSAY, ELISA
reproductive tract:	HE4	CEA	Immunohistochemistry
cervical, uterine,	SAA	AFP
ovarian		CA15-3
		CA125
Cancer of male	PSA	PSA	Immunoassay
reproductive organ: prostrate testis	PHI 4KSCORE	AFP HCG-BETA	Immunohistochemistry
Lung cancer	NCAM, IL-2R, IGF-I, transferrin, ANP,	CEA	Immunoassay, PCR, ELISA
	mAb (cluster 5), CYFRA 21	SCC	Immunohistochemistry,
		ALK	PCR, ELISA
		CYFRA 21-1
Thyroid cancer	Galectin	Calcitonin	Immunoassay
	BRAF	CEA	Immunohistochemistry,
		Thyroglobulin	PCR

PCR: Polymerase Chain Reaction, IHC: Immunohistochemistry, ELISA: Enzyme-linked immunosorbent assay, CA: Cancer antigen, CEA: Carcinoembryonic antigen, ER: Estrogen receptor, PR: Progesterone receptor, p53: Tumor suppressor, HER: Heregulin, TPA: Serum tissue polypeptide antigen, TPS: Tissue polypeptide-specific antigen, BRAF: proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, FOBT: The fecal occult blood test, EGFR: Epidermal growth factor receptor, KRAS: Kirsten rat sarcoma viral oncogene homolog, PIK3CA: Phosphatidylinositol 3-kinase, ALK: Anaplastic lymphoma kinase, PDL1: Programmed death-ligand 1, HE4: Human epididymis protein 4, OPN: Osteopontin, IGFR: Insulin-like growth factor receptor, VGEF: Vascular endothelial growth factor, MMP: Matrix metalloproteinase, MAGE: Tumor-specific antigen, ZEB: Zinc finger E-box binding homeobox, PTEN: Phosphatase and tensin homolog, BUB: Mitotic checkpoint protein, MYC: Basic helix-loop-helix protein, THCA: tetrahydrocannabinol acid, TSHR: Thyroid-stimulating hormone receptor, TTR: Transthyretin, GPC: Glypican, MIB: Cellular marker for proliferation, BTA: Bladder tumor antigen, HCG: Human chorionic gonadotropin, CYFRA: Cytokeratin fragment, PHI: Prostate Health Index, 4KSCORE: Kallikrein markers, ANP: Natriuretic peptide, SCC: Squamous cell carcinoma antigen, CK: Cytokeratin’s, PSA: Prostate specific antigen, AFP: Alpha-fetoprotein, PKM2: Pyruvate kinase M2, IGFBP2: Insulin-Like Growth factor binding protein 2, LOH: Loss of Heterozygosity, TNIK: NICK-interactive kinase, PAI-1: Plasminogen activator inhibitor 1, up A: Urokinase plasminogen activator

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

Tumor	Blood markers
Head-and-neck cancer	SCC antigen
	CA 125
	CEA
	DNA ploidy
Lung cancer	FHIT
	ALK
Colorectal cancer	MLH 1, PTEN, MSH 2, MSH 6, MMR, KRAS
Male reproductive	PSA
system	PHI
Bladder cancer	HCG BETA, CEA, NMP22
Pancreatic cancer	CA19-9
Liver cancer	Alpha-fetoprotein, ERCC1
Thyroid cancer	Thyroglobin
Breast cancer	BRAC1, HE4, MIF, leptin, OPN, CA 125, p53
Female reproductive system	Microsatellite, P53, beta cantenin, PTEN, HER2/NEU, KRAS
Stomach cancer	CA 72-4
Esophageal cancer	CEA
	PDL1
Skin cancer	BRAF

CA: Cancer Antigen, CEA: Carcinoembryonic antigen, ER: Estrogen receptor, PR: Progesterone receptor, p53: tumor suppressor, HER: Heregulin, BRAF: Proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, EGFR: Epidermal growth factor receptor, KRAS: Kirsten rat sarcoma viral oncogene homolog, PIK3CA: Phosphatidylinositol 3-kinase, ALK: Anaplastic lymphoma kinase, PDL1: Programmed death-ligand 1, HE4: Human epididymis protein 4, OPN: Osteopontin, PTEN: Phosphatase and tensin homolog, HCG: Human chorionic gonadotropin, CYFRA: Cytokeratin fragment, PHI: Prostate Health Index, SCC: Squamous cell carcinoma antigen, PSA: Prostate-specific antigen, AFP: Alpha-fetoprotein., FHIT: Fragile histidine triad

CONCLUSION

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.