Published date: Jun 30 2021

Journal Title: Sudan Journal of Medical Sciences

Issue title: Sudan JMS: Volume 16 (2021), Issue No. 2

Pages: 207–222

DOI: 10.18502/sjms.v16i2.9289

Monica DugăeșescuFundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Florentina MușatUniversity Emergency Hospital of Bucharest, Romania

Octavian AndronicUniversity Emergency Hospital of Bucharest, Romania

Background: Epidermal growth factor (EGF) is a stimulating protein for cell proliferation and differentiation. An amplification of its signaling pathway has been frequently reported in numerous malignant tumors. Specific polymorphisms of the genes encoding proteins involved in this cellular pathway may constitute risk factors for carcinogenesis. The aim of this study was to identify the most relevant polymorphisms of EGF and their signaling pathways and their relation to carcinogenesis.

Methods: The study included 40 full-text articles published between January 2010 and May 2020, extracted from PubMed, Scopus, Web of Science, and Science Direct databases in May 2020, using the following keywords: EGF OR epidermal growth factor AND polymorphism AND cancer OR neoplasia OR tumor.

Results: We identified relevant polymorphisms of the EGF signaling pathway that were involved in the development and progression of hepatocellular carcinoma, esophageal cancer, gastric cancer, colorectal cancer, glioma, lung cancer, breast cancer, cervical cancer, and head and neck cancer. Rs4444903 variants have been widely studied and the association with numerous tumors has been confirmed by multiple studies. Other frequently investigated polymorphisms are –191C/A and –216G>T.

Conclusion: The polymorphisms of EGF signaling pathway have been widely studied in connection to various malignancies. Some predisposing variants are common in different forms of cancer. These polymorphisms might be general risk factors for carcinogenesis.

Keywords: epidermal growth factor, cancer, polymorphism, signaling pathway

[1] Shen, W., Tian, Y., Ran, T., et al. (2015). Genotyping and quantification techniques for single-nucleotide polymorphisms. Trends in Analytical Chemistry, vol. 69, pp. 1–13. Retrieved from: https://linkinghub. elsevier.com/retrieve/pii/S0165993615000953


[2] Hanchard, N. A. (2005). Genetic susceptibility and single-nucleotide polymorphisms. Seminars in Fetal & Neonatal Medicine, vol. 10, no. 3, pp. 283–289. Retrieved from: https://linkinghub.elsevier.com/ retrieve/pii/S1744165X05000090


[3] Fareed, M. and Afzal, M. (2013). Single nucleotide polymorphism in genome-wide association of human population: a tool for broad spectrum service. Egyptian Journal of Medical Human Genetics, vol. 14, no. 2, pp. 123–134. Retrieved from: https://linkinghub.elsevier.com/retrieve/pii/S1110863012000687


[4] Normanno, N., De Luca, A., Bianco, C., et al. (2006). Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, vol. 366, no. 1, pp. 2–16. Retrieved from: https://linkinghub.elsevier.com/retrieve/pii/ S0378111905006347


[5] Zeng, F. and Harris, R. C. (2014). Epidermal growth factor, from gene organization to bedside. Seminars in Cell and Developmental Biology, vol. 28, pp. 2–11. Retrieved from: https://linkinghub.elsevier.com/ retrieve/pii/S1084952114000135


[6] Esquirol Caussa, J. and Herrero Vila, E. (2015). Epidermal growth factor, innovation and safety. Med Clínica, vol. 145, no. 7, pp. 305–312. Retrived from: https://linkinghub.elsevier.com/retrieve/pii/ S2387020616000930


[7] Yuan, J. M., Fan, Y., Ognjanovic, S., et al. (2013). Genetic polymorphisms of epidermal growth factor in relation to risk of hepatocellular carcinoma: two case-control studies. BMC Gastroenterology, vol. 13, no. 1, p. 32. Retrieved from: https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-13-32


[8] Suenaga, M., Yamada, S., Fujii, T., et al. (2013). A functional polymorphism in the epidermal growth factor gene predicts hepatocellular carcinoma risk in Japanese hepatitis C patients. OncoTargets and Therapy, vol. 6, pp. 1805–1812. Retrieved from: http://www.dovepress.com/a-functional-polymorphismin-the-epidermal-growth-factor-gene-predicts-peer-reviewed-article OTT


[9] Abu Dayyeh, B. K., Yang, M., Fuchs, B. C., et al. (2011). A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology, vol. 141, no. 1, pp. 141–149. Retrieved from: https://linkinghub.elsevier.com/retrieve/pii/S0016508511004161


[10] Shi, H. Z., Ren, P., Lu, Q. J., et al. (2012). Association between EGF, TGF-β1 and TNF-α gene polymorphisms and hepatocellular carcinoma. Asian Pacific Journal of Cancer Prevention, vol. 13, no. 12, pp. 6217–6220. Retrieved from: http://koreascience.or.kr/journal/view.jsp?kj=POCPA9&py= 2012&vnc=v13n12&sp=6217


[11] Jiang, G., Yu, K., Shao, L., et al. (2015). Association between epidermal growth factor gene +61A/G polymorphism and the risk of hepatocellular carcinoma: a meta-analysis based on 16 studies. BMC Cancer, vol. 15, no. 1, p. 314. Retrieved from: http://bmccancer.biomedcentral.com/articles/10.1186/ s12885-015-1318-6


[12] Zhong, J. H., You, X. M., Gong, W. F., et al. (2012). Epidermal growth factor gene polymorphism and risk of hepatocellular carcinoma: a meta-analysis. PLoS ONE, vol. 7, no. 3, p. e32159. Retrieved from: https://dx.plos.org/10.1371/journal.pone.0032159


[13] Yang, Z., Wu, Q., Shi, Y., et al. (2012). Epidermal growth factor 61A>G polymorphism is associated with risk of hepatocellular carcinoma: a meta-analysis. Genetic Testing and Molecular Biomarkers, vol. 16, no. 9, pp. 1086–1091. Retrieved from: http://www.liebertpub.com/doi/10.1089/gtmb.2012.0050


[14] Li, Y. L., Tian, Z., Zhao, L., et al. (2014). Association between the EGF rs4444903 polymorphism and liver cancer susceptibility: a meta-analysis and meta-regression. Genetics and Molecular Research, vol. 13, no. 4, pp. 8066–8079. Retrieved from: http://www.funpecrp.com.br/gmr/year2014/vol13-4/pdf/ gmr3575.pdf


[15] Zhang, Y., Zhang, J., Shen, N., et al. (2016). EGF rs4444903a allele may decrease hepatocellular carcinoma risk in chinese individuals: a meta-analysis. International Journal of Clinical and Experimental Medicine, vol. 9, no. 3, pp. 5719–5727. Retrieved from: http://www.ijcem.com/files/ijcem0009615.pdf


[16] Sun, S., Jin, G. J., Zhao, Y., et al. (2015). Association between the epidermal growth factor 61*A/G polymorphism and hepatocellular carcinoma risk: a meta-analysis. Asian Pacific Journal of Cancer Prevention, vol. 16, no. 7, pp. 3009–3014. Retrieved from: http://koreascience.or.kr/journal/view.jsp?kj= POCPA9&py=2015&vnc=v16n7&sp=3009


[17] Li, W. Q., Hu, N., Wang, Z., et al. (2013). Genetic variants in epidermal growth factor receptor pathway genes and risk of esophageal squamous cell carcinoma and gastric cancer in a Chinese population. PLoS One, vol. 8, no. 7, e68999. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/23874846


[18] Zhang, J., Zhan, Z., Wu, J., et al. (2013). Association among polymorphisms in EGFR gene exons, lifestyle and risk of gastric cancer with gender differences in Chinese Han subjects. PLoS ONE, vol. 8, no. 3, e59254. Retrieved from: https://dx.plos.org/10.1371/journal.pone.0059254


[19] Zhan, Z., Chen, Y., Wu, J., et al. (2013). Functional epidermal growth factor gene polymorphisms and risk of gastric cancer. Oncology Letters, vol. 5, no. 2, pp. 631–636. Retrived from: https://www.spandidospublications.com/10.3892/ol.2012.1041


[20] Torres-Jasso, J. H., Marín, M. E., Luna Santiago, E. S., et al. (2015). EGFR gene polymorphisms -216G>T and -191C>A are risk markers for gastric cancer in Mexican population. Genetics and Molecular Research, vol. 14, no. 1, pp. 1802–1807. Retrieved from: http://www.funpecrp.com.br/gmr/year2015/ vol14-1/pdf/gmr4537.pdf


[21] Peng, Q., Li, S., Qin, X., et al. (2014). EGF +61A/G polymorphism contributes to increased gastric cancer risk: evidence from a meta-analysis. Cancer Cell International, vol. 14, no. 1, p. 134. Retrieved from: http://cancerci.biomedcentral.com/articles/10.1186/s12935-014-0134-4


[22] Araújo, A. P., Costa, B. M., Pinto-Correia, A. L., et al. (2011). Association between EGF +61A/G polymorphism and gastric cancer in caucasians. World Journal of Gastroenterology, vol. 17, no. 4, pp. 488–492. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027015/


[23] Chaleshi, V., Haghighi, M. M., Savabkar, S., et al. (2013). Correlation between the EGF gene intronic polymorphism, rs2298979, and colorectal cancer. Oncology Letters, vol. 6, no. 4, pp. 1079–1083. Retrieved from: https://www.spandidos-publications.com/10.3892/ol.2013.1481


[24] Mustafa, O. H., Hamzeh, A. R., Ghabreau, L., et al. (2013). Allele frequencies of the epidermal growth factor receptors polymorphism R521K in colorectal cancer patients and healthy subjects indicate a risk-reducing effect of K521 in Syrian population. North American Journal of Medical Sciences, vol. 5, no. 3, pp. 202–206. Retrieved from: http://www.najms.org/text.asp?2013/5/3/202/109189


[25] Zhu, X., Shen, Y., and Xie, Q. (2019). The association between EGF A61G polymorphism and risk of colorectal cancer in a Chinese population: a case-control study. Bioscience Reports, vol. 39, no. 5, BSR20190495. Retrieved from: https://portlandpress.com/bioscirep/article/doi/10.1042/BSR20190495/ 219161/The-association-between-EGF-A61G-polymorphism-and


[26] Lau, T. P., Roslani, A. C., Lian, L. H., et al. (2014). Association between EGF and VEGF functional polymorphisms and sporadic colorectal cancer in the Malaysian population. Genetics and Molecular Research, vol. 13, no. 3, pp. 5555–5561. Retrieved from: http://www.funpecrp.com.br/gmr/year2014/ vol13-3/pdf/gmr3635.pdf


[27] Chaleshi, V., Haghighi, M. M., Javadi, G. R., et al. (2013). The effect of 5’untranslated region polymorphism in EGF gene, rs4444903, on colorectal cancer. Gastroenterology and Hepatology From Bed to Bench, vol. 6, no. 3, pp. 129–135. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/24834259


[28] Zhu, Y., Chen, Z. H., Jiang, H. G., et al. (2019). The genetic association between EGF A61G polymorphism (rs4444903) and risk of colorectal cancer: an update meta-analysis and trial sequential analysis. Medicine, vol. 98, no. 2, e14007. Retrieved from: http://journals.lww.com/00005792-201901110-00041


[29] Costa, B. M., Viana-Pereira, M., Fernandes, R., et al. (2011). Impact of EGFR genetic variants on glioma risk and patient outcome. Cancer Epidemiology, Biomarkers & Prevention, vol. 20, no. 12, pp. 2610–2617. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/21960689


[30] Hou, W. G., Ai, W. B., Bai, X. G., et al. (2012). Genetic variation in the EGFR gene and the risk of glioma in a Chinese Han population. PLoS ONE, vol. 7, no. 5, e37531. Retrieved from: https://dx.plos.org/10. 1371/journal.pone.0037531


[31] Wang, S., Zhao, Y., Ruan, Z., et al. (2010). Association between EGF +61 G/A and glioma risk in a Chinese population. BMC Cancer, vol. 10, p. 221. Retrieved from: http://bmccancer.biomedcentral.com/articles/ 10.1186/1471-2407-10-221


[32] Chen, X., Yang, G., Zhang, D., et al. (2014). Association between the epidermal growth factor +61G/ A polymorphism and glioma risk: a meta-analysis. PLoS ONE, vol. 9, no. 4, e95139. Retrieved from: https://dx.plos.org/10.1371/journal.pone.0095139


[33] Tan, D., Xu, J., Li, Y., et al. (2010). Association between +61G polymorphism of the EGF gene and glioma risk in different ethnicities: a meta-analysis. Tohoku Journal of Experimental Medicine, vol. 222, no. 4, pp. 229–235. Retrieved from: http://joi.jlc.jst.go.jp/JST.JSTAGE/tjem/222.229?from=CrossRef


[34] Xu, X., Xi, L., Zeng, J., et al. (2012). A functional +61G/A polymorphism in epidermal growth factor is associated with Glioma risk among asians. PLoS ONE, vol. 7, no. 7, e41470. Retrieved from: https: //dx.plos.org/10.1371/journal.pone.0041470


[35] Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., et al. (2013). Epidermal Growth Factor Receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic White women: The Breast Cancer Health Disparities Study. International Journal of Molecular Epidemiology and Genetics, vol. 4, no. 4, pp. 235–249. Retrieved from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid= PMC3852643


[36] Abdraboh, N. R., Shehata, H. H., Ahmed, M. B., et al. (2013). HER1 R497K and HER2 I655V polymorphisms are linked to development of breast cancer. Disease Markers, vol. 34, no. 6, pp. 407–17. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810125/


[37] de Almeida, F. C., Banin Hirata, B. K., Ariza, C. B., et al. (2018). HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility. Journal of Clinical Laboratory Analysis, vol. 1, no. 6, e22406. Retrieved from: http://doi.wiley.com/10.1002/jcla.22406


[38] Bashir, N. A., Morad, F. R., Khabour, O. F., et al. (2019). The EGFR rs2233947 polymorphism is associated with lung cancer risk: a study from Jordan. Acta Biochimica Polonica, vol. 66, no. 3, pp. 315–319. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/31518089


[39] Bashir, N. A., Ragab, E. S., Khabour, O. F., et al. (2018). The association between epidermal growth factor receptor (EGFR) gene polymorphisms and lung cancer risk. Biomolecules, vol. 8, no. 3, p. 53. Retrieved from: http://www.mdpi.com/2218-273X/8/3/53


[40] Beg, M. M. A., Fahdil, S. R., Yadav, P., et al. (2019). Association of EGFR 1 gene alteration and their association with lung adenocarcinoma patients. Asian Pacific Journal of Cancer Prevention, vol. 20, no. 3, pp. 825–830. Retrieved from: http://journal.waocp.org/article_82575.html


[41] Liu, C., Xu, X., and Zhou, Y. (2015). Association between EGFR polymorphisms and the risk of lung cancer. International Journal of Clinical and Experimental Pathology, vol. 8, no. 11, pp. 15245–15249. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/26823874


[42] Masroor, M., Amit, J., Javid, J., et al. (2015). Clinical implication of EGF A61G polymorphism in the risk of non small cell lung adenocarcinoma patients: a case control study. Asian Pacific Journal of Cancer Prevention, vol. 16, no. 17, pp. 7529–7534. Retrieved from: http://koreascience.or.kr/journal/view.jsp?kj= POCPA9&py=2015&vnc=v16n17&sp=7529


[43] Chen, Q., Zheng, Y., Wu, B., et al. (2020). Association between polymorphisms of epidermal growth factor 61 and susceptibility of lung cancer. Medicine, vol. 99, no. 17, e19456. Retrieved from: https: //journals.lww.com/10.1097/MD.0000000000019456


[44] Xin, D. J., Shen, G. D., and Song, J. (2015). Single nucleotide polymorphisms of HER2 related to osteosarcoma susceptibility. International Journal of Clinical and Experimental Pathology, vol. 8, no. 8, pp. 9494–9499. Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/26464710


[45] Ma, D., Hovey, R. L., Zhang, Z., et al. (2013). Genetic variations in EGFR and ERBB4 increase susceptibility to cervical cancer. Gynecologic Oncology, vol. 131, no. 2, pp. 445–450. Retrieved from: https://linkinghub.elsevier.com/retrieve/pii/S0090825813010780


[46] Fung, C., Zhou, P., Joyce, S., et al. (2015). Identification of epidermal growth factor receptor (EGFR) genetic variants that modify risk for head and neck squamous cell carcinoma. Cancer Letters, vol. 357, no. 2, pp. 549–556. Retrieved from: https://linkinghub.elsevier.com/retrieve/pii/S0304383514007514


[47] Bolocan, A., Stoian, R. V., Ion, D., et al. (2012). Peculiarities of diagnosis and treatment in the polypcancer sequence. Chirurgia, vol. 107, no. 1, pp. 66–70. Retrieved from: http://www.ncbi.nlm.nih.gov/ pubmed/22480119