Association between EGF +61G/A Polymorphisms and Prognosis in Hepatocellular Carcinoma
Keywords:
HCC, DNA polymorphisms, genotype, allele, EGF, PCR-RFLP, prognosisAbstract
Introduction: Epidermal growth factor (EGF) gene is located on chromosome 4q25-27. Its
functions have been associated with proliferation, differentiation, tumor growth, invasion and
metastasis in several cancers including hepatocellular carcinoma (HCC).
Objective:To examine the association between EGF +61G/A polymorphisms and carcinogenesis
of hepatocellular carcinoma, clinicopathological parameters as well as the overall survival of
patients with HCC.
Material and Methods: Polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP) was performed for determination of EGF +61G/A polymorphisms in 254 healthy
control samples and 76 HCC patients.
Results: The frequencies of GG, GA and AA genotypes were 44.09 (112/254), 46.85 (119/254)
and 9.05 (23/254) respectively, in the healthy control group, while the HCC patients group
exhibited 39.47 (30/76), 57.89 (44/76) and 2.63 (2/76) respectively. Furthermore, the frequency
of G and A alleles were 67.52 (343/508) and 32.48 (165/508) respectively, in the healthy control
subjects and 68.42 (104/152) and 31.58 (48/152) respectively, in the HCC patients. There was no
association between EGF +61G/A polymorphisms and carcinogenesis of HCC. While, we found
that EGF 61 +G/A genotype of GA+AA was significantly correlated with tumor grade II (p = 0.01)
and had a good prognosis in patient with HCC when comparing with GG genotype (p = 0.01,
median survival 22 and 7 months, respectively).
Conclusions: There was no association between EGF 61 +G/A polymorphisms and
hepatocarcinogenesis. However, this study was found the correlation between GA+AA genotype
and low tumor grading and good prognosis in Thai HCC patients.
References
P, Chiawiriyabunya I, Namthaisong K,
Wongsena M, et al. Cancer in Thailand,
Vol. IX, 9, 2018.
2. อาคม ชัยวีระวัฒนะ, อาคม เชียรศิลป์, เสาวคนธ์
ศุกรโยธิน และธีรวุฒิ คูหะเปรมะ. แนวทางการ
ตรวจวินิจฉัยและรักษาโรคมะเร็งตับและมะเร็ง
ท่อน้ำดี. สถาบันมะเร็งแห่งชาติ กรมการแพทย์
กระทรวงสาธารณสุข.
3. Salomon DS, Brandt R, Ciardiello F,
Normanno N. Epidermal growth factorrelated peptides and their receptors
in human malignancies. Crit Rev Oncol
Hematol. 1995; 19: 183-232.
4. Normanno N, Bianco C, De Luca A, Salomon
DS. The role of EGF-related peptides
in tumor growth. Front Biosci. 2001; 6:
D685–707.
5. Groenen LC, Nice EC, Burgess AW. Structurefunction relationships for the EGF/TGFalpha family of mitogens. Growth Factors.
1994; 11: 235-57.
6. Jorissen RN, Walker F, Pouliot N, Garrett
TP, Ward CW, Burgess AW. Epidermal
growth factor receptor: mechanisms of
activation and signalling. Exp Cell Res.
2003; 284: 31-53.
7. Stoscheck CM, King LE Jr. Role of epidermal
growth factor in carcinogenesis. Cancer
Res. 1986; 46: 1030-7.
8. Lazar-Molnar E, Hegyesi H, Toth S, Falus
A. Autocrine and paracrine regulation by
cytokines and growth factors in melanoma.
Cytokine. 2000; 12: 547–54.
9. Jiang G, Yu K, Shao L, Yu X, Hu C, Qian
P, et al. Association between epidermal
growth factor gene +61A/G polymorphism
and the risk of hepatocellular carcinoma:
a meta-analysis based on 16 studies. BMC
Cancer. 2015; 15: 314.
10. Baghdadi I, Ella KA, Shaaraway AE, Elshayeb
E, El-Rebey HS, Hoseeny ME, et al. Genetic
Polymorphism of Epidermal Growth Factor
Gene as a Predictor of Hepatocellular
Carcinoma in Hepatitis C Cirrhotic Patients.
Asian Pac J Cancer Prev. 2020; 21: 2047-53.
11. Henson ES, Gibson SB. Surviving cell death
through epidermal growth factor (EGF)
signal transduction pathways: implications
for cancer therapy. Cell Signal. 2006;
18(12): 2089-97.
12. Shahbazi M, Pravica V, Nasreen N, Fakhoury
H, Fryer AA, Strange RC, et al. Association
between functional polymorphism in EGF
gene and malignant melanoma. Lancet.
2002; 359: 397-401.
13. Bhowmick DA, Zhuang Z, Wait SD, Weil
RJ. Functional polymorphism in the EGF
gene is found with increased frequency in
glioblastoma multiforme patients and is
associated with more aggressive disease.
Cancer Res. 2004; 64: 1220-3.
14. Lanuti M, Liu G, Goodwin JM, Zhai
R, Fuchs BC, Asomaning K, et al. A
functional epidermal growth factor (EGF)
polymorphism, EGF serum levels, and
esophageal adenocarcinoma risk and
outcome. Clin Cancer Res. 2008; 14: 3216-
22.
15. Zhu X, Shen Y, Xie Q. The association
between EGF A61G polymorphism and
risk of colorectal cancer in a Chinese
population: a case-control study. Biosci
Rep. 2019; 39: SR20190495
16. Tanabe KK, Lemoine A, Finkelstein
DM, Kawasaki H, Fujii T, Chung RT,
et al. Epidermal growth factor gene
functional polymorphism and the risk of
hepatocellular carcinoma in patients with
cirrhosis. JAMA. 2008; 299: 53-60.
17. Abu Dayyeh BK, Yang M, Fuchs BC, Karl DL,
Yamada S, Sninsky JJ, et al. HALT-C Trial
Group. A functional polymorphism in the
epidermal growth factor gene is associated
with risk for hepatocellular carcinoma.
Gastroenterology. 2011; 141: 141-9.
18. Cui L, Pan XM, Ma CF, Guan JS, Yu HB,
Chen GX, et al. Association between
epidermal growth factor polymorphism
and esophageal squamous cell carcinoma
susceptibility. Dig Dis Sci. 2010; 55: 40-5.
19. Ktistaki E, Talianidis I, Modulation of
Hepatic Gene Expression by Hepatocyte
Nuclear Factor 1. Science. 1997; 277, 109-
12
20. Li Y, Xie Q, Lu F, Zhao J, Mao P, Li Z,
et al. Association between epidermal
growth factor 61A/G polymorphism and
hepatocellular carcinoma susceptibility in
Chinese patients. Liver Int. 2010; 30: 112-8.
21. Okamoto I, Roka F, Krögler J, Endler
G, Kaufmann S, Tockner S, et al. The
EGF A61G polymorphism is associated
with disease-free period and survival in
malignant melanoma. J Invest Dermatol.
2006; 126: 2242-6.
22. Jain M, Kumar S, Upadhyay R, Lal P, Tiwari
A, Ghoshal UC, et al. Influence of apoptosis
(BCL2, FAS), cell cycle (CCND1) and growth
factor (EGF, EGFR) genetic polymorphisms
on survival outcome: an exploratory study
in squamous cell esophageal cancer.
Cancer Biol Ther. 2007; 6: 1553-8.
23. Jin G, Miao R, Deng Y, Hu Z, Zhou Y, Tan
Y, et al. Variant genotypes and haplotypes
of the epidermal growth factor gene
promoter are associated with a decreased
risk of gastric cancer in a high-risk Chinese
population. Cancer Sci. 2007; 98: 864-8.
24. Hamai Y, Matsumura S, Matsusaki K,
Kitadai Y, Yoshida K, Yamaguchi Y, et al.
A single nucleotide polymorphism in the
5’ untranslated region of the EGF gene is
associated with occurrence and malignant
progression of gastric cancer. Pathobiology.
2005; 72: 133-8.
