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Dear Label_Name,

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I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
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American Journal of Medical Sciences and Medicine
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American Journal of Pharmacological Sciences
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American Journal of Cancer Prevention
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American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
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Tumor Markers of Colorectal Carcinoma: New Perspectives

Ahmed M. Kabel*, Shaimaa M. Kabel

Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt

Abstract: Colorectal carcinoma (CRC) represents one of the most commonly diagnosed malignant tumors worldwide. In spite of the continuous progress in diagnostic and therapeutic tools, CRC significantly contributes to cancer-related deaths all over the world. Early detection and treatment of patients with CRC may have a positive impact on prognosis, as the delay of diagnosis carries the risk of poor prognosis. Recently, new tumor biomarkers were discovered which can alone or together with the existing tests recognize either the predisposing factors or the early stages of CRC. Also, these biomarkers have the potential to determine the appropriate treatment algorithms by selecting the proper chemotherapeutic agents that can induce remission in a broad spectrum of patients. This review throws light on the tumor markers of CRC and their role in early diagnosis and determination of prognosis and the suitable lines of management of patients with CRC.

Keywords: colorectal cancer, tumor markers, diagnosis, management

Received January 19, 2024; Revised February 20, 2024; Accepted March 01, 2024

Citation: Ahmed M. Kabel, Shaimaa M. Kabel, Tumor Markers of Colorectal Carcinoma: New Perspectives. Journal of Cancer Research and Treatment, 12 (1). 1-7. January 2024. doi:10.12691/jcrt-12-1-1

1. Introduction

Colorectal cancer (CRC) is one of the common malignancies that may affect one million male and female patients annually and causes more than half a million deaths worldwide [1]. In Europe in 2010, CRC was considered to be the third most widespread malignant tumor in both males and females [2]. The recently available data report that the overall five-year relative survival rate may reach about 65%, but it varies depending on the stage of the tumor [3].

The National Institute of Health defines a biomarker as a biological molecule found in blood, body fluids, or tissues that represents a sign of abnormal or normal process, or of a condition or a disease [4]. Some researchers considered a tumor code marker as an alternative to biomarkers [5]. It refers to substances representing biological structures, which can be attributed to the development of normal cells or carcinogenesis at different cell development stages e.g., tumor-associated antigens (TAAs) which are the large group of clinically significant markers [6]. Consequently, TAAs concentrations typically correlate with the number or mass of neoplastic cells [7].

Recently, the researchers are constantly searching for new diagnostic methods that would be able to early detect CRC. Neoplastic markers can be able to determine a quantity of glycoproteins and glycolipids in blood of patients with CRC [8]. The neoplastic markers have participated in diagnosis of gastrointestinal neoplasms, mainly in early post-operative detection of repetition of neoplastic disease and in evaluation of the efficacy of surgery [9]. As demonstrated in Figure 1, various biomarkers are commonly used in the clinical practice for proper diagnosis, monitoring of therapy, and prediction of prognosis of CRC.

Figure 1. Tumor markers of colorectal carcinoma

According to the European Group on Tumor Markers (EGTM), carcinoembryonic antigen (CEA) is the main marker used in detection of CRC [6]. However, approximately 10-15 % of patients are unable to produce CEA or could secrete a little amount. Therefore, the use of cancer antigen (CA) 19-9 as a tumor marker in diagnosis of CRC has been proposed [10]. This review sheds light on the tumor markers of CRC and their role in early diagnosis and determination of prognosis and the suitable lines of management of patients with CRC with special emphasis on the most commonly used biomarkers.

2. Blood and Stool Genetic and Epigenetic Markers

Many authors had investigated molecular noninvasive examination tests for early detection of CRC.DNA, RNA and other molecules derived by tumor in feces, as well as their concentrations in blood have been elaborated extensively [11]. Colorectal carcinogenesis is described by genetic and epigenetic factors that transform normal cells into cancer cells [12]. Epigenetic changes have been detected in CRC patients with 70%-96% sensitivity and 72%-96% specificity [13]. Numerous combinations of genetic and epigenetic markers had been studied. Using blood in place of stool as a screening material could offer some advantages [14].

The use of RNA biomarkers in stool has not been investigated as widely as was the case for DNA biomarkers, fundamentally because the responsible cause for degradation of mRNA is stool environment, although improving laboratory recovery methods appear to solve this problem [15]. Sensitivity was thought to be more related to the tumor size and its location, rather than to the tumor stage [16]. Several studies had evaluated mRNA of different tumor genes in complete blood, plasma or circulating tumor cells to recognize new CRC screening markers. Most of them investigated mRNA molecules of CK19, CK20, or carcinoembryonic antigen (CEA) [17]. Recent studies had indicated that circulating miRNAs may be involved in the process of oncogenesis [16]. The use of miRNA as a biomarker is now under- evaluated. A major number of miRNA molecules have been assessed, with a focus on miR145, miR143, miR135 and miR17-92 [18].

3. Blood and Stool Protein Markers

Protein markers for screening and early detection of CRC include tumor-associated antigens (TAAs), antibodies against TAAs, and other CRC-relevant proteins [19]. CEA was discovered about 55 years ago and is still the only recognized tumor marker for monitoring efficacy of CRC patients’ therapy [20]. High CEA concentrations are only rarely identified in CRC stage I. Furthermore, CEA does not differentiate benign versus malignant polyps [21]. According to The European Group on Tumor Markers, CEA is not recommended for use in screening tests [22]. In some studies, elevated CEA concentrations in patients with CRC stage II and III were found to be potentially indicative of more aggressive kinds of cancer. Previously, the Colorectal Working Group of American Joint Committee on Cancer suggested to include CEA baseline concentration to the traditional TNM classification as the so-called C-stage [6].

The role of CEA in prediction of life expectancy was approved in several studies on patients with liver metastases [23]. It was demonstrated that the use of CEA and serum amyloid A (SAA) as combination is able to determine patients with favorable and poor prognosis [24]. CEA half-life is known to last about 7 days. Slow elevation in CEA concentrations after surgery is an irregular sign of local recurrence, while dynamically rising levels can be symptomatic of liver metastasis [25]. CEA is the first marker of choice for observation of disseminated disease during systemic treatment [20]. CEA concentration can also be elevated temporarily as a result of using chemotherapy [26]. So, it is not recommended to test CEA levels within 2 weeks of chemotherapy, while in patients on oxaliplatin, tests can be carried out after 4 to 6 weeks [6].

The plurality of researchers concluded that CA 19-9 sensitivity is much inferior to that of CEA, and that increased CA19-9 levels is a poor prognostic value [27]. CA 72-4 is a biomarker with poor sensitivity ranging from 9% to 31% and better specificity ranging from 89% to 95% in patients screened for CRC [28]. Many authors concluded that CA 72-4 sensitivity is partly low with incomplete specificity in screening and following up in patients with CRC [20].

4. Molecular Biomarkers Used for Prediction of Prognosis

With the recent progress in understanding the molecular mechanisms of cancer development, dissemination, resistance to chemotherapy, and radiation therapy, the selection of the most appropriate strategy for managing CRC is now easier than before [6]. Clinical prospective and retrospective studies open the gate for biomarkers use in clinical practice to support in choosing the best drugs. Biomarker identification is predominately important for patients with CRC stage II [29]. The markers discovered during the recent years include microsatellite instability (MSI), chromosome 18q lack of heterozygosity (18qLOH), p53, PTEN expression, UGT1A1 gene polymorphism, and ezrin protein [30].

4.1. Microsatellite Instability (MSI)

MSI indicates changes in coding and non-coding sequences of microsatellite chromosomes. Microsatellite instability can be categorized into microsatellite instability-high (MSI-H), and microsatellite instability-low (MSI-L), based on the percentage of loci that correlate to MSI characteristics [31]. Tumor cells that lack MSI features are designated as MSS. In retrospective studies and meta-analyses in patients with CRC stage II and III, MSI-H was shown to be a predictive factor that improved overall survival, irrespective of the stage of cancer [32].

MSI status is presently recommended in the WHO classification of mucinous-type CRC. MSI-H indicates good prognosis while MSI-L or MSS indicates poor outcome [31]. However, MSI should be considered more of a prognostic rather than predictive value [6]. This conclusion depends on results of studies evaluating the efficacy of 5-fluorouracil based chemotherapy in patients with MSI-H and MSI-L or MSS tested tumor specimens collected from 570 patients with CRC stage II and III and correlated the test results with chemotherapy outcomes in these patients to show a tendency for shorter overall survival in patients with MSI-H on adjuvant therapy. Significant improvement was observed in patients with MSS tumors [33].

4.2. Chromosome 18q Loss of Heterozygosity

Many studies were dedicated to another prognostic factor in patients with CRC stage II and III - chromosome 18q lack of heterozygosity in the coding place of, inter alia, SMAD 4 proteins specific to CRC [34]. In these studies, the total 5-year survival was poorer for patients with CRC stage III and 18qLOH as compared to non-18qLOH patients. Furthermore, no correlation was identified between the presence of 18qLOH and 5-year survival in patients with non-MSI-H phenotype [35]. Depending on the available information, 18q chromosome deletion cannot be on a single basis for any therapeutic decisions [36].

4.3. P53 Mutation

About 50%-70% of all CRC patients are vulnerable to mutations in the tumor suppressor gene p53 [37]. This mutation is also associated with worse outcomes, including disease free survival and overall survival rates [38]. Patients with p53 mutation and tumour of proximal colon had preferable overall survival rate when treated with adjuvant chemotherapy in comparison to those treated with surgery alone [6].

5. Biomarkers Suitable in Anti-Epidermal Growth Factor Receptor Therapy

A number of currently tested markers have been discovered in the course of studies on epidermal growth factor receptor (EGFR) signaling pathways [39]. KRAS gene mutation on short arm of chromosome 12 at codon 12 or, to a lesser extent, at codon 13 is believed to be used as a biomarker in patients on cetuximab or panitumumab [40]. These mutations are one of the most common in proliferative diseases and their significance in CRC carcinogenesis has been examined [6]. As these mutations are present in EGFR signalling pathway, they can be a predictive factor for therapy with anti-EGFR antibodies. Cetuximab improves the therapeutic outcomes with non-KRAS patients [41].

V600E mutation was the most frequently observed BRAF mutation. BRAF mutations make the tumor resistant to anti-EGFR monoclonal antibodies, and significantly worsen prognosis, especially in patients with MSI-L and MSS [42]. Strongly synergistic reaction when adding cetuximab with BRAF inhibitors was observed. Since NRAS mutation can predict resistance to EGFR therapy, NRAS mutation testing should be considered when KRAS is mutation negative [43].

Phosphatidylinositide-3-kinases (PI3K) are kinases that enhance cellular proliferation. Mutations in PIK3CA gene have been identified in several human solid tumors, including CRC [44]. PIK3CA gene is mutated in 10%-20% of CRC tumors. Recent studies have detected an increase in colon cancer-specific mortality in patients with PIK3CA-mutated tumors, as compared with patients with PIK3CA wild-type tumors [45].

The presence of PIK3CA mutation was reported to be correlated with a significant increase in CRC specific mortality, through patients with KRAS wild-type tumors [46]. Recent studies have found that suppression of cyclooxygenase-2 by regular use of aspirin after CRC diagnosis was associated with longer cancer specific survival time through patients with mutated compared to wild-type PIK3CA [47]. PIK3CA mutations may serve as a predictive biomarker for adjuvant aspirin therapy [46].

6. Biomarkers of the Potential Toxicity of Irinotecan

Irinotecan is an antineoplastic enzyme inhibitor primarily used for treatment of CRC. It is a derivative of camptothecin that inhibits the action of topoisomerase I, and inhibiting replication and stimulating cell apoptosis [48]. The most common adverse effects of irinotecan are intensive diarrhoea caused by damaged intestinal epithelium and advanced neutropenia. Polymorphism of the UGT1A1 gene is a very useful biomarker of the potential toxicity of irinotecan [6]. According to a recent meta-analysis study, genotyping for UGT1A1 has no predictive value in terms of responsiveness to different doses of irinotecan in patients with CRC [49].

7. Potential Biomarkers of Vascular Endothelial Growth Factor-Targeted Therapy

Since the vascular endothelial growth factor (VEGF)-targeted therapy has been incorporated into CRC treatment protocols, several anti-angiogenic drugs have been introduced (e.g. bevacizumab) [50]. Various studies on identification of predictive biomarkers of bevacizumab have been performed. High baseline values of VEGF were associated with worse progression free survival and the overall survival rate [51]. Other studies had proven that plasma VEGF-A may serve as a prognostic marker, but is incapable to predict response to VEGF-targeted therapy in advanced CRC [6].

Ezrin protein, a part of ezrin/radixin/moesin family may play a significant role in tumor invasion process [52]. Recent studies have found that overexpression of ezrin protein correlates with CRC aggressiveness [53]. Ezrin may represent a relevant biomarker and target for personalized anti-metastatic therapies [54].

8. Diagnostic Tissue Markers

Immunohistochemistry (IHC) is usually used for diagnosis of gastrointestinal neoplasms to facilitate accurate tumor classification [6]. IHC is used to affirm tumor analysis by barring morphologic mimickers and to recognize the most sensible tissue or organ of source in cases of metastatic carcinoma of unknown primary [55]. Also, the results of IHC give important prognostic data and even anticipate responsiveness to standard chemotherapy or novel molecular targeted therapy. Analytic tissue biomarkers accordingly give extra and essential data that complement clinical colonoscopy findings [56].

8.1. Cytokeratins

The cytokeratins (CKs) that belong to the group of intermediate filaments along with glial filaments, neurofilaments, desmin, and vimentin, are proteins communicated by epithelial cells [57]. Non-neoplastic colonic mucosa proximal to the rectum shows a CK7−/CK20+ phenotype, as do 90% of CRC [58]. The main other neoplasms to exhibit this CK7−/CK20+ phenotype in a significant extent of cases are Merkel cell carcinoma and a fraction of gastric adenocarcinomas [6].

8.2. CDX2

CDX2 is an interpretation factor encoded by CDX2, a part of the caudal subgroup of homeobox genes [59]. It is fundamental for embryonic and lifelong maintenance of a cellular intestinal phenotype [60]. CDX2 is strongly expressed in epithelial cells of the normal small intestine, appendix, colon, and rectum as well as the centroacinar and interacinar ductal cells of the pancreas [61].

8.3. Villin

Villin is a differentiation marker of the brush border which has a diagnostic role in human renal cell carcinoma. The specificity of villin as a marker of intestinal origin is limited [62]. This may be attributed to the fact that similar CDX2 appearance might be observed in adenocarcinomas with intestinal separation emerging from an assortment of sites including the stomach, lung, and ovary and additionally, seldom, in malignancies of other places such as the endocervix and liver [63].

8.4. Carcinoembryonic Antigen

Monoclonal CEA may be communicated in a wide assortment of adenocarcinomas, including those emerging from the colon [64]. Although this lack of specificity bounds its general utility as an indicative marker of CRC, it remains a helpful marker for diagnosis of CRC [6].

8.5. Alpha-methyl Acyl-CoA Racemase

Alpha-methyl acyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that is implicated in beta-oxidation of branched-chain fatty acids [65]. Among the different types of malignancies, AMACR protein expression is frequently seen in adenocarcinomas of the colon and prostate [66]. Increased AMACR expression in the colonic adenomas and carcinomas implies that it has an important role in colorectal carcinogenesis [67]. Interestingly, decreased AMACR expression in high grade colorectal carcinomas may be taken as a proof of its role in malignant differentiation of the colonic tissues [68].

8.6. Cadherin 17

Cadherin-17 (CDH17) is a calcium-dependent transmembrane glycoprotein that mediates cell–cell adhesion in intestinal epithelium [69]. Expression of CDH17 was reported in gastric, pancreatic, and colorectal adenocarcinomas [6]. It is seldom found in adenocarcinomas from outside the gastrointestinal tract. Strangely, although CDH17 is tran-scriptionally controlled by CDX2, few researchers observed it to be slightly more sensitive and specific than CDX2 in distinguishing colorectal adenocarcinomas [70].

9. Prognostic Tissue Markers

High Special AT-rich sequence-binding protein 2 (SATB2) expression was related with good prognosis in colon cancer and might balance affect ability to chemotherapy and radiation, while decreased expression of SATB2 in colorectal adenocarcinomas was observed to be related to poor prognosis, containing tumor invasion, lymph node metastasis, and distant metastasis [71]. In addition, loss of CDX2 expression is related with proximal location, infiltrative growth, advanced stage and is an independent poor prognostic factor of general survival and progression-free survival [72].

10. Predictive Tissue Markers

10.1. BRAF V600E IHC

In CRC, BRAF V600E is the most common mutation [26]. BRAF V600E mutation in MSI CRCs can virtually exclude Lynch syndrome, and mutation positive tumors are resistant to anti-epithelial growth factor receptor (EGFR) therapy [73]. BRAF V600E IHC is a sensitive and reliable assay, generating outcomes that correlated well with those from molecular detection methods [13].

10.2. Epithelial-to-Mesenchymal Transition (EMT) and Drug Resistance

An increasing number of findings suggest that tumors undergoing EMT resist conventional drug therapy [18]. In clinical practice, tumor specimens taken from CRC patients who have received preoperative chemotherapy followed by radical surgery display phenotypic changes characteristic of and molecular changes consistent with the EMT [27]. Consistently, loss of E-cadherin stimulates drug resistance in CRC patients and the recurrent tumors have a significantly EMT-like signature [74].

10.3. EGFR Expression and EGFR Targeted Therapy Predictive Markers

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with an intracellular tyrosine kinase domain [41]. Binding of ligands to the EGFR promotes tumor growth and progression by controlling transcription, cell cycle progression, apoptosis and differentiation through the EGFR downstream signaling pathway [75]. EGFR monoclonal antibodies (e.g. cetuximab and panitumumab) are active drugs in combination chemotherapy or as monotherapy for metastatic CRC [76].

10.4. CD133 As a Potential Marker for Traditional and Targeted Treatment

CD133 is a surface protein commonly used for isolation of colon cancer stem cells. It is associated with tumor angiogenesis and recurrence [77]. The patients with high gene expression levels of CD133 showed a significantly greater tumor response than patients with low expression levels, independent of the expression of VEGF or its receptors [78].

10.5. P53

P53 is encoded by TP53 gene, located on the short arm of chromosome 17 [79]. P53 is a transcription factor and one of most commonly investigated tumor suppresso genes [80]. Many functions have been recognized for p53 including repair of damaged DNA, block of cellular cycle, and induction of apoptosis. Its alterations are frequent at early stage in natural history of many cancers [81]. However, its main disadvantage is of lack of specificity [35].

10.6. Familial Adenomatous Polyposis (FAP)

FAP is an autosomal dominant condition characterized by hundreds to thousands of adenomas in the colon and rectum [82]. It has been proven to be responsible for about 0.5% of all cases of CRC [83]. Approximately 70–80% of patients with classical FAP harbor germline mutations in the APC gene [6]. Screening for FAP should commence with a detailed family history. For individuals with suspected FAP, genetic testing can be used both to confirm diagnosis and to assess the risk in presymptomatic family members [84]. Provided that the mutation responsible for FAP within a family is known, testing for APC mutations can be considered for at risk family members [41]. ed for at risk family members.

11. Conclusion

The tumor markers of CRC play a major role in better understanding of this disease and help in the development of new therapeutic strategies, especially in advanced metastatic cases. These markers include blood and stool genetic and epigenetic markers, blood and stool protein markers and biomarkers used for prediction of prognosis. Implementation of the primary care services may effectively decrease the burden and improve the prognosis of CRC.

Conflict of Interest

The authors had no conflict of interest to declare.

Funding

This study didn’t receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

[1]   | Shao B, Zhu M, Shen K, Luo L, Du P, Li J, Xu J, Deng Y, Lin N, Wu J, Hu W. Disease Burden of Total and Early-Onset Colorectal Cancer in China from 1990 to 2019 and Predictions of Cancer Incidence and Mortality. Clin Epidemiol. 2023; 15: 151-163.
[2]   | Topdagi O, Timuroglu A. Eighteen Years’ Retrospective Review of Colorectal Cancer Cases in Eastern Population. Eurasian J Med 2018; 50(1): 19-22.
[3]   | Dutta A, Pratiti R, Kalantary A, Aboulian A, Shekherdimian S. Colorectal Cancer: A Systematic Review of the Current Situation and Screening in North and Central Asian Countries. Cureus. 2023; 15(1): e33424.
[4]   | Bodaghi A, Fattahi N, Ramazani A. Biomarkers: Promising and valuable tools towards diagnosis, prognosis and treatment of Covid-19 and other diseases. Heliyon. 2023; 9(2): e13323.
[5]   | Thannickal HH, Eltoum N, Henderson NL, Wallner LP, Wagner LI, Wolff AC, Rocque GB. Physicians' Hierarchy of Tumor Biomarkers for Optimizing Chemotherapy in Breast Cancer Care. Oncologist. 2024; 29(1): e38-e46.
[6]   | Lech G, Słotwiński R, Słodkowski M, Krasnodębski IW. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances. World J Gastroenterol 2016; 22(5): 1745-55.
[7]   | Zhu Q, Liu M, Dai L, Ye H, Han S, Zhang J-Y. Using immunoproteomics to identify tumor-associated antigens (TAAs) as biomarkers in cancer immunodiagnosis. Autoimmun rev 2013; 12(12): 1123-8.
[8]   | Sarhadi VK, Armengol G. Molecular Biomarkers in Cancer. Biomolecules 2022; 12(8): 1021.
[9]   | Kabel AM, Abd Elmaaboud MA. Cancer: Role of Nutrition, Pathogenesis, Diagnosis and Management. World Journal of Nutrition and Health 2014; 2(4): 48-51.
[10]   | Vukobrat-Bijedic Z, Husic-Selimovic A, Sofic A, Bijedic N, Bjelogrlic I, Gogov B, et al. Cancer Antigens (CEA and CA 19-9) as Markers of Advanced Stage of Colorectal Carcinoma. Med Arch 2013; 67(6):397-401.
[11]   | Danese E, Montagnana M. Epigenetics of colorectal cancer: emerging circulating diagnostic and prognostic biomarkers. Ann Transl Med 2017; 5(13): 279.
[12]   | Ajithkumar P, Vasantharajan SS, Pattison S, McCall JL, Rodger EJ, Chatterjee A. Exploring Potential Epigenetic Biomarkers for Colorectal Cancer Metastasis. Int J Mol Sci. 2024; 25(2): 874.
[13]   | Li X, Li J, Li J, Liu N, Zhuang L. Development and validation of epigenetic modification-related signals for the diagnosis and prognosis of colorectal cancer. BMC Genomics. 2024; 25(1): 51.
[14]   | Stürzlinger H, Conrads-Frank A, Eisenmann A, et al. Stool DNA testing for early detection of colorectal cancer: systematic review using the HTA Core Model® for Rapid Relative Effectiveness Assessment. Ger Med Sci 2023; 21: Doc06.
[15]   | Bustin SA, Murphy J. RNA biomarkers in colorectal cancer. Methods 2013; 59(1): 116-25.

[16]  
Pekarek L, Torres-Carranza D, Fraile-Martinez O, García-Montero C, Pekarek T, Saez MA, Rueda-Correa F, Pimentel-Martinez C, Guijarro LG, Diaz-Pedrero R, Alvarez-Mon M, Ortega MA. An Overview of the Role of MicroRNAs on Carcinogenesis: A Focus on Cell Cycle, Angiogenesis and Metastasis. Int J Mol Sci. 2023; 24(8): 7268.

[17]   | Fadaka AO, Pretorius A, Klein A. Biomarkers for Stratification in Colorectal Cancer: MicroRNAs. Cancer Control 2019; 26(1): 1073274819862784.
[18]   | Chen B, Xia Z, Deng YN, Yanfang Yang Y, Zhang P, Zhu H, et al. Emerging microRNA biomarkers for colorectal cancer diagnosis and prognosis. Open Biol 2019; 9(1): 180212.
[19]   | Toma SC, Ungureanu BS, Patrascu S, Surlin V, Georgescu I. Colorectal Cancer Biomarkers- A New Trend in Early Diagnosis. Curr Health Sci J 2018; 44(2): 140-6.
[20]   | Liu HN, Yao C, Wang XF, et al. Diagnostic and economic value of carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4 in gastrointestinal cancers. World J Gastroenterol. 2023; 29(4) :706-30.
[21]   | Hall C, Clarke L, Pal A, Buchwald P, Eglinton T, Wakeman C, et al. A Review of the Role of Carcinoembryonic Antigen in Clinical Practice. Ann Coloproctol 2019; 35(6): 294-305.

[22]  
Liao L, Tang J, Hong Z, Jiang W, Li Y, Kong L, Han K, Hou Z, Zhang C, Zhou C, Zhang L, Sui Q, Xiao B, Mei W, Yu J, Yang W, Pan Z, Ding PR. The effects of oxaliplatin-based adjuvant chemotherapy in high-risk stage II colon cancer with mismatch repair-deficient: a retrospective study. BMC Cancer. 2024; 24(1): 164.

[23]  
Wach MM, Nunns G, Hamed A, Derby J, Jelinek M, Tatsuoka C, Holtzman MP, Zureikat AH, Bartlett DL, Ahrendt SA, Pingpank JF, Choudry MHA, Ongchin M. Normal CEA Levels After Neoadjuvant Chemotherapy and Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion Predict Improved Survival from Colorectal Peritoneal Metastases. Ann Surg Oncol. 2024 Jan 25.

[24]   | Tong G, Xu W, Zhang G, Liu J, Zheng Z, Chen Y, et al. The role of tissue and serum carcinoembryonic antigen in stages I to III of colorectal cancer-A retrospective cohort study. Cancer Med 2018; 7(11): 5327-38.
[25]   | Holm M, Saraswat M, Joenväärä S, Ristimäki A, Haglund C, Renkonen R. Colorectal cancer patients with different C-reactive protein levels and 5-year survival times can be differentiated with quantitative serum proteomics. PLoS One 2018; 13(4): e0195354.
[26]   | Bardet S, Ciappuccini R, Lamartina L, Leboulleux S. Unusual increase in carcinoembryonic antigen despite response to selpercatinib in two patients with medullary thyroid cancer. Eur Thyroid J. 2022; 11(2): e210104.
[27]   | Saito G, Sadahiro S, Kamata H, Miyakita H, Okada K, Tanaka A, et al. Monitoring of Serum Carcinoembryonic Antigen Levels after Curative Resection of Colon Cancer: Cutoff Values Determined according to Preoperative Levels Enhance the Diagnostic Accuracy for Recurrence. Oncology 2017; 92(5): 276-82.
[28]   | Ning S, Wei W, Li J, Hou B, Zhong J, Xie Y, Liu H, Mo X, Chen J, Zhang L. Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients. J Cancer. 2018; 9(3): 494-501.
[29]   | Shin JK, Kim HC, Lee WY, Yun SH, Cho YB, Huh JW, et al. High preoperative serum CA 19-9 levels can predict poor oncologic outcomes in colorectal cancer patients on propensity score analysis. Ann Surg Treat Res 2019; 96(3): 107-15.
[30]   | Vacante M, Borzì AM, Basile F, Biondi A. Biomarkers in colorectal cancer: Current clinical utility and future perspectives. World J Clin Cases 2018; 6(15): 869-81.
[31]   | Duan L, Yang W, Wang X, Zhou W, Zhang Y, Liu J, et al. Advances in prognostic markers for colorectal cancer. Expert Rev Mol Diagn 2019; 19(4): 313-24.
[32]   | Zeinalian M, Hashemzadeh-Chaleshtori M, Salehi R, Emami MH. Clinical Aspects of Microsatellite Instability Testing in Colorectal Cancer. Adv Biomed Res 2018; 7: 28.
[33]   | Kang S, Na Y, Joung SY, Lee SI, Oh SC, Min BW. The significance of microsatellite instability in colorectal cancer after controlling for clinicopathological factors. Medicine (Baltimore) 2018; 97(9): e0019.
[34]   | Jo WS, Carethers JM. Chemotherapeutic implications in microsatellite unstable colorectal cancer. Cancer Biomark 2006; 2(1-2): 51-60.
[35]   | Armaghany T, Wilson JD, Chu Q, Mills G. Genetic alterations in colorectal cancer. Gastrointest Cancer Res. 2012; 5(1): 19-27.
[36]   | Wang W, Li YF, Sun XW, Chen G, Zhan YQ, Huang CY, et al. Correlation analysis between loss of heterozygosity at chromosome 18q and prognosis in the stage-II colon cancer patients. Chin J Cancer 2010; 29(8): 761-7.
[37]   | Nguyen HT, Duong HQ. The molecular characteristics of colorectal cancer: Implications for diagnosis and therapy. Oncol Lett 2018; 16(1): 9-18.
[38]   | Wang D, Nakayama M, Hong CP, Oshima H, Oshima M. Gain-of-Function p53 Mutation Acts as a Genetic Switch for TGFβ Signaling-Induced Epithelial-to-Mesenchymal Transition in Intestinal Tumors. Cancer Res. 2024; 84(1): 56-68.
[39]   | Chen LC, Yang PC, Chen CY, Chiang SF, Chen TW, Chen WT, Ke TW, Liang JA, Shiau AC, Chao KSC, Huang KC. Dual Inhibition of B7-H3 and EGFR Overcomes Acquired Chemoresistance in Colon Adenocarcinoma. J Cancer. 2024; 15(6): 1750-1761.
[40]   | Nakayama M, Oshima M. Mutant p53 in colon cancer. J Mol Cell Biol 2019; 11(4): 267-76.
[41]   | Sforza V, Martinelli E, Ciardiello F, Gambardella V, Napolitano S, Martini G, et al. Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer. World J Gastroenterol 2016; 22(28): 6345-61.
[42]   | Patel JN, Fong MK, Jagosky M. Colorectal Cancer Biomarkers in the Era of Personalized Medicine. J Pers Med 2019; 9(1): 3.
[43]   | Bond CE, Whitehall VLJ. How the BRAF V600E Mutation Defines a Distinct Subgroup of Colorectal Cancer: Molecular and Clinical Implications. Gastroenterol Res Pract 2018; 2018: 9250757.
[44]   | Afrăsânie VA, Marinca MV, Alexa-Stratulat T, Gafton B, Păduraru M, Adavidoaiei AM, et al. KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer - practical implications for the clinician. Radiol Oncol 2019; 53(3): 265-74.
[45]   | Wang Q, Shi YL, Zhou K, Wang LL, Yan ZX, Liu YL, et al. PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis 2018; 9(7): 739.
[46]   | Mei ZB, Duan CY, Li CB, Cui L, Ogino S. Prognostic role of tumor PIK3CA mutation in colorectal cancer: a systematic review and meta-analysis. Ann Oncol 2016; 27(10): 1836-48.
[47]   | Hall DCN, Benndorf RA. Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited. Cell Mol Life Sci. 2022;79(7): 393.
[48]   | Hamada T, Nowak JA, Ogino S. PIK3CA mutation and colorectal cancer precision medicine. Oncotarget 2017; 8(14): 22305-6.
[49]   | Rodrigues D, Longatto-Filho A, Martins SF. Predictive Biomarkers in Colorectal Cancer: From the Single Therapeutic Target to a Plethora of Options. Biomed Res Int 2016; 2016: 6896024.
[50]   | Cortejoso L, García MI, García-Alfonso P, González-Haba E, Escolar F, Sanjurjo M, et al. Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer. Cancer Chemother Pharmacol 2013; 71(6): 1463-72.
[51]   | Balasubramanian S, Priyathersini N, Johnson T. Expression of Vascular Endothelial Growth Factor (VEGF) in Colorectal Adenoma and Carcinoma in a Tertiary Care Center. Cureus. 2022; 14(11): e31393.
[52]   | Jang HJ, Kim BJ, Kim JH, Kim HS. The addition of bevacizumab in the first-line treatment for metastatic colorectal cancer: an updated meta-analysis of randomized trials. Oncotarget 2017; 8(42): 73009-16.
[53]   | Kobori T, Tanaka C, Tameishi M, Urashima Y, Ito T, Obata T. Role of Ezrin/Radixin/Moesin in the Surface Localization of Programmed Cell Death Ligand-1 in Human Colon Adenocarcinoma LS180 Cells. Pharmaceuticals (Basel). 2021; 14(9): 864.
[54]   | Fathi A, Mosaad H, Hussein S, Roshdy M, Ismail EI. Prognostic significance of CD133 and ezrin expression in colorectal carcinoma. IUBMB Life 2017; 69(5): 328-40.
[55]   | Leiphrakpam PD, Rajput A, Mathiesen M, Agarwal E, Lazenby AJ, Are C, et al. Ezrin expression and cell survival regulation in colorectal cancer. Cell Signal 2014; 26(5): 868-79.
[56]   | Bărbălan A, Nicolaescu AC, Măgăran AV, Mercuţ R, Bălăşoiu M, Băncescu G, et al. Immunohistochemistry predictive markers for primary colorectal cancer tumors: where are we and where are we going?. Rom J Morphol Embryol 2018; 59(1): 29-42.
[57]   | Theiss AP, Chafin D, Bauer DR, Grogan TM, Baird GS. Immunohistochemistry of colorectal cancer biomarker phosphorylation requires controlled tissue fixation. PLoS One 2014; 9(11): e113608.
[58]   | Pastuszak M, Groszewski K, Pastuszak M, Dyrla P, Wojtuń S, Gil J. Cytokeratins in gastroenterology. Systematic review. Prz Gastroenterol 2015; 10(2): 61-70.

[59]  
Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgó E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MF. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. N Engl J Med. 2016; 374(3): 211-22.

[60]   | Haraldsson S, Klarskov L, Nilbert M, Bernstein I, Bonde J, Holck S. Differential expression of CK20, β-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X. BMC Clin Pathol 2017; 17: 11.
[61]   | Tomasello G, Barni S, Turati L, Ghidini M, Pezzica E, Passalacqua R, et al. Association of CDX2 Expression With Survival in Early Colorectal Cancer: A Systematic Review and Meta-analysis. Clin Colorectal Cancer 2018; 17(2): 97‐103.

[62]  
Dum D, Lennartz M, Menz A, Kluth M, Hube-Magg C, Weidemann S, Fraune C, Luebke AM, Hornsteiner L, Bernreuther C, Simon R, Clauditz TS, Sauter G, Uhlig R, Hinsch A, Kind S, Jacobsen F, Möller K, Wilczak W, Steurer S, Minner S, Burandt E, Marx AH, Krech T, Lebok P. Villin expression in human tumors: a tissue microarray study on 14,398 tumors. Expert Rev Mol Diagn. 2022; 22(6): 665-675.

[63]   | Graule J, Uth K, Fischer E, Centeno I, Galván JA, Eichmann M, et al. CDX2 in colorectal cancer is an independent prognostic factor and regulated by promoter methylation and histone deacetylation in tumors of the serrated pathway. Clin Epigenetics 2018;10(1):120.
[64]   | Li Z, Rock JB, Roth R, Lehman A, Marsh WL, Suarez A, et al. Dual Stain With SATB2 and CK20/Villin Is Useful to Distinguish Colorectal Carcinomas From Other Tumors. Am J Clin Pathol 2018; 149(3): 241-6.
[65]   | Gatalica Z, Stafford P, Vranic S. Alpha-methylacyl-CoA racemase (AMACR) protein is upregulated in early proliferative lesions of the breast irrespective of apocrine differentiation. Hum Pathol. 2022; 129: 40-46.

[66]  
Kabel, A. M., Ashour, A. M., Ali, D. A., & Arab, H. H. (2021). The immunomodulatory effects of topiramate on azoxymethane-induced colon carcinogenesis in rats: The role of the inflammatory cascade, vascular endothelial growth factor, AKT/mTOR/MAP kinase signaling and the apoptotic markers. International immunopharmacology, 98, 107830.

[67]   | Kaushal A, Kaur N, Sharma S, Sharma AK, Kala D, Prakash H, Gupta S. Current Update on Biomarkers for Detection of Cancer: Comprehensive Analysis. Vaccines (Basel). 2022 Dec 13; 10(12): 2138.
[68]   | Shukla N, Adhya AK, Rath J. Expression of Alpha - Methylacyl - Coenzyme A Racemase (AMACR) in Colorectal Neoplasia. J Clin Diagn Res 2017; 11(4): EC35‐EC38.
[69]   | Ku SC, Liu HL, Su CY, Yeh IJ, Yen MC, Anuraga G, Ta HDK, Chiao CC, Xuan DTM, Prayugo FB, Wang WJ, Wang CY. Comprehensive analysis of prognostic significance of cadherin (CDH) gene family in breast cancer. Aging (Albany NY). 2022; 14(20): 8498-8567.
[70]   | Abouelkhair, M. B., Mabrouk, S. H., Zaki, S. S. A., Nada, O. H., & Hakim, S. A. (2021). The Diagnostic Value of Cadherin 17 and CDX2 Expression as Immunohistochemical Markers in Colorectal Adenocarcinoma. Journal of gastrointestinal cancer, 52(3), 960–9.
[71]   | Zhang YJ, Chen JW, He XS, Zhang HZ, Ling YH, Wen JH, et al. SATB2 is a Promising Biomarker for Identifying a Colorectal Origin for Liver Metastatic Adenocarcinomas. EBioMedicine 2018; 28: 62-9.
[72]   | Ma C, Olevian D, Miller C, Herbst C, Jayachandran P, Kozak MM, et al. SATB2 and CDX2 are prognostic biomarkers in DNA mismatch repair protein deficient colon cancer. Mod Pathol 2019; 32(8): 1217-31.
[73]   | Ducreux M, Chamseddine A, Laurent-Puig P, Smolenschi C, Hollebecque A, Dartigues P, et al. Molecular targeted therapy of BRAF-mutant colorectal cancer. Ther Adv Med Oncol 2019; 11: 1758835919856494.
[74]   | Druzhkova I, Ignatova N, Prodanets N, Kiselev N, Zhukov I, Shirmanova M, et al. E-Cadherin in Colorectal Cancer: Relation to Chemosensitivity. Clin Colorectal Cancer 2019; 18(1): e74‐e86.
[75]   | Gnosa SP, Puig Blasco L, Piotrowski KB, Freiberg ML, Savickas S, Madsen DH, Auf dem Keller U, Kronqvist P, Kveiborg M. ADAM17-mediated EGFR ligand shedding directs macrophage-promoted cancer cell invasion. JCI Insight. 2022; 7(18): e155296.
[76]   | García-Foncillas J, Sunakawa Y, Aderka D, Wainberg Z, Ronga P, Witzler P, et al. Distinguishing Features of Cetuximab and Panitumumab in Colorectal Cancer and Other Solid Tumors. Front Oncol 2019; 9: 849.
[77]   | Akbari M, Shomali N, Faraji A, Shanehbandi D, Asadi M, Mokhtarzadeh A, et al. CD133: An emerging prognostic factor and therapeutic target in colorectal cancer. Cell Biol Int 2020; 44(2): 368-80.
[78]   | Abdou Hassan W, Muqresh MA, Omer M. The Potential Role of CD44 and CD133 in Colorectal Stem Cell Cancer. Cureus. 2022; 14(10): e30509.
[79]   | Rivlin 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(4): 466-74.
[80]   | Kabel AM. Tumor protein p53: Novel aspects of an old tumor marker. J Cancer Res Treat 2015; 3(2): 25-7.
[81]   | Zawacka-Pankau JE. The Role of p53 Family in Cancer. Cancers (Basel). 2022; 14(3): 823.
[82]   | Bojuwoye MO, Olokoba AB, Ogunlaja OA, Agodirin SO, Ibrahim OK, Okonkwo KC, et al. Familial adenomatous polyposis syndrome with colorectal cancer in two Nigerians: a report of two cases and review of literature. Pan Afr Med J 2018; 30: 6.
[83]   | Karstensen JG, Bülow S, Højen H, Jelsig AM, Jespersen N, Andersen KK, Wewer MD, Burisch J, Pommergaard HC. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. Gastroenterology. 2023; 65(3): 573-581.e3.
[84]   | Long JM, Powers JM, Katona BW. Evaluation of Classic, Attenuated, and Oligopolyposis of the Colon. Gastrointest Endosc Clin N Am. 2022; 32(1): 95-112.