Meta-Analysis of Epidermal Growth Factor Polymorphisms and Cancer Risk: Involving 9,779 Cases and 15,932 Controls

Abstract

The epidermal growth factor (EGF) pathway stimulates proliferation and differentiation of epidermal and epithelial tissues, and plays an important role in tumorigenesis. The association between EGF polymorphisms and cancer risk is controversial; thus, we performed this meta-analysis. Overall, 41 case–control studies with 9,779 cases and 15,932 controls were retrieved. We found that EGF +61A/G polymorphism increased overall cancer risk (G allele vs. A allele: OR=1.181, 95% CI=1.077–1.295, P _{heterogeneity} < 0.001; GG vs. AA: OR=1.370, 95% CI=1.143–1.641, P _{heterogeneity} < 0.001; GG+GA vs. AA: OR=1.175, 95% CI=1.047–1.318, P _{heterogeneity} < 0.001). In the stratified analysis by cancer type, the +61 G allele was a risk factor for colorectal cancer, esophageal carcinoma, gastric cancer, and hepatocellular carcinoma. Individuals who carried +61G allele had higher cancer susceptibility in mixed and European racial subgroups. An increased association was detected in the hospital-based subgroup. No significant association was found among EGF −1380A/G, −1744G/A, rs6983267T/G polymorphisms and cancer risk.

Introduction

C ancer is the leading cause of death in economically developed countries and the second leading cause of death in developing countries (World Health Organization, 2008). The burden of cancer is increasing in economically developing countries as a result of population aging and growth as well as an adoption of cancer-associated lifestyle choices including smoking, physical inactivity, and “westernized” diets (Jemal et al., 2011). A great part of genetic polymorphism between individuals is due to the presence of single-nucleotide polymorphisms (SNPs). These SNPs predispose individuals to different types of cancer (Dong et al., 2008). Numerous genome-wide explorations for common cancers have revealed a number of loci in the genome that have low-penetrance cancer susceptibility (Wokolorczyk et al., 2008; Harismendy and Frazer, 2009; Zintzaras, 2010). Recently, many studies have investigated the risk of cancer associated with the polymorphisms in epidermal growth factor (EGF) gene, including breast cancer (Wang et al., 2008; Araújo et al., 2009b), cervical cancer (Kang et al., 2007b; Araújo et al., 2011a), colorectal cancer (Chen et al., 2009; Wu et al., 2009; Daraei et al., 2011), esophageal carcinoma (Lanuti et al., 2008; Cheung et al., 2009; Cui et al., 2010), gastric cancer (Goto et al., 2005; Hamai et al., 2005; Jin et al., 2007; Araújo et al., 2011b), glioma (Bhowmick et al., 2004; Costa et al., 2007; Vauleon et al., 2007; Liu et al., 2009; Pinto et al., 2009; Bao et al., 2010; Wang et al., 2010), hepatocellular carcinoma (Tanabe et al., 2008; Qi et al., 2009; Li et al., 2010; Abu Dayyeh et al., 2011; Chen et al., 2011), lung cancer (Lim et al., 2005; Kang et al., 2007a), melanoma (Shahbazi et al., 2002; McCarron et al., 2003; Amend et al., 2004; James et al., 2004; Randerson-Moor et al., 2004; Casula et al., 2009), and so on (Gao et al., 2008; Vishnoi et al., 2008; Araújo et al., 2009a; Almeida et al., 2010; Wu et al., 2010; Yuan et al., 2011). EGF, located on chromosome 4q25-q27 (Normanno et al., 2006), contains 24 exons and 23 introns and encodes a ligand for the EGF receptor (EGFR). As an endocrine growth factor, EGF can activate DNA synthesis, cellular differentiation, and cellular proliferation via binding to EGFR. EGF is overexpressed in malignant glioma, breast, pancreas, and liver carcinomas, indicating its vital role in malignant cell transformation, tumor occurrence and development by promoting cell division via autocrine or paracrine pathways, EGFR gene amplification, and activating mutations (Jorissen et al., 2003; Limaye et al., 2008).

Shahbazi et al. (2002) first reported a functional SNP involving an A-to-G mutation at position 61 of the 5′-untranslated region of the EGF gene (rs4444903) in 2002. They demonstrated that the G allele increased EGF protein expression by affecting DNA folding or mRNA transcript in vitro and revealed that patients with malignant melanoma of skin had a significantly higher frequency of G allele compared with the general population. Jin et al. (2007) first found two SNPs (−1380A/G and −1744G/A) in the promoter region of EGF. They reported no significant association between −1380A/G polymorphism and gastric cancer; however, the −1744 G allele played a protective role. Moreover, Daraei et al. (2011) reported that rs6983267 G allele in the 8q24 region was a risk factor in the development of colorectal cancer.

To evaluate the effects of these four EGF promoter SNPs and cancer susceptibility, we analyzedt genotypes among SNPs of +61A/G, −1380A/G, −1744G/A, and rs6983267 in 9,779 cases and 15,932 controls.

Materials and Methods

Identification and eligibility of relevant studies

We searched the PubMed database, last search updated on August 1, 2011, with the keywords containing “EGF” or “epidermal growth factor,” “polymorphism” or “variant,” and “cancer” or “carcinoma,” without any restriction on language or publication year. Using these terms, a total of 122 articles were retrieved, of which 41 articles met the inclusion criteria. We also screened reference of the retrieved articles and review articles by hand.

Inclusion criteria and exclusion criteria

Studies that were included in our analysis met all of the following criteria: (a) the study assessed the correlation between cancer risk and EGF polymorphisms, (b) case–control studies, and (c) sufficient genotype numbers for cases and controls. Accordingly, the following exclusion criteria were also used: (a) no control population, (b) no available genotype frequency, and (c) duplication of the previous publications.

Data extraction

Two of the authors extracted all data independently. The following items were collected: first author's last name, year of publication, country of origin, ethnicity, cancer type, total case/control number, source of control, Hardy–Weinberg equilibrium (HWE) of controls, and genotyping methods.

Statistical analysis

Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of the association between EGF polymorphisms and cancer risk based on the genotype frequencies in cases and controls. Subgroup analysis stratified by cancer type was performed first. If one cancer type was reported in only one individual study, it is classified to the “others” subgroup. Ethnicity was categorized as European, Asian, and mixed. Source of control subgroup analysis was performed on two classifications: population based (PB) and hospital based (HB).

The fixed effects model and the random effects model were used to calculate the pooled OR value. The statistical significance of the summary OR was determined with the Z-test. Heterogeneity assumption was evaluated with a chi-square–based Q-test among the studies. A p value of more than 0.05 for the Q-test indicated a lack of heterogeneity among the studies. In case significant heterogeneity was detected, the random effects model (DerSimonian-Laird method) was used; however, the fixed effects model (Mantel-Haenszel method) was chosen (Mantel and Haenszel, 1959; DerSimonian and Laird, 1986). We investigated the relationship between EGF genetic variants and cancer risk in allelic contrast (G allele vs. A allele for +61A/G and −1380A/G; A allele vs. G allele for −1744G/A; G-allele vs. T-allele for rs6983267), homozygote comparison (GG vs. AA for +61A/G and −1380A/G; AA vs. GG for −1744G/A; GG vs. TT for rs6983267), and dominant genetic model (GG+GA vs. AA for +61A/G and −1380A/G; AA+AG vs. GG for −1744G/A; GG+GT vs. TT for rs6983267). Sensitivity analysis was performed by omitting each study in turn to assess the stability of the results. The departure of frequencies of EGF polymorphisms from expectation under HWE was assessed by χ ² test in controls using the Pearson chi-square test; p<0.05 was considered significant. All statistical tests for this meta-analysis were performed with Stata software (version 10.0; StataCorp LP, College Station, TX).

Genotyping methods

Genotyping for four SNPs in EGF gene within the studies analyzed was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), primer introduced restriction analysis-polymerase chain reaction (PIRA-PCR), matrix-assisted laser desorption ionization-time of flight (MALDI-TOF), polymerase chain reaction–single strand conformation polymorphism (PCR-SSCP), Taqman and ARMS test.

Results

Study selection and characteristics in the meta-analysis

A total of 122 articles was identified: 13 review articles were excluded, 1 duplicated article was also excluded (if two studies with overlapping data were published by the same investigators, only the most recent or complete study was included in our meta-analysis.) (Qi et al., 2008, 2009). Overall, 41 case–control studies with 9,779 cases and 15,932 controls were retrieved based on the search criteria for whole cancer susceptibility related to the four EGF polymorphisms. The controls were mainly healthy populations. If one study contained two or more races as its research subjects, we consider it mixed. In our study, there were 18 European case–control studies, 19 Asian case–control studies, and 4 mixed case–control studies for +61A/G; two Asian studies for −1380A/G and −1744G/A; and one Asian study for rs6983267. The controls in 26 studies were HB and 15 were PB for +61A/G. For the +61A/G polymorphism, the G allele frequency of Asians was significantly higher than mixed individuals in controls (p<0.001); moreover, the mixed population that carried the G allele was significantly higher than Europeans (p=0.001) (Fig. 1). A similar trend was found in cases. The distribution of genotypes in all the controls was in agreement with HWE, except for four studies (Shahbazi et al., 2002; Vauleon et al., 2007; Abu Dayyeh et al., 2011; Araújo et al., 2011b).

FIG. 1.

Frequencies of the epidermal growth factor +61G allele among control subjects stratified by ethnicity.

Meta-analysis

Table 1 shows the summary OR of EGF +61A/G on the basis of 9,779 cancer cases and 15,932 controls. Overall, we observed an increased association between the EGF +61A/G polymorphism and cancer risk in all three genetic models (G allele vs. A allele: OR=1.181, 95% CI=1.077–1.295, P _{heterogeneity}<0.001; GG vs. AA: OR=1.370, 95% CI=1.143–1.641, P _{heterogeneity}<0.001; GG+GA vs. AA: OR=1.175, 95% CI=1.047–1.318, P _{heterogeneity}<0.001). In the subgroup by cancer type, significantly increased relationships were found in four kinds of cancers (colorectal cancer: G allele vs. A allele, OR=1.144, 95% CI=1.060–1.235, P _{heterogeneity}=0.100; GG vs. AA, OR=1.293, 95% CI=1.138–1.469, P _{heterogeneity}<0.001; GG+GA vs. AA, OR=1.064, 95% CI=1.000–1.132, P _{heterogeneity}=0.119; esophageal carcinoma: G allele vs. A allele, OR=1.168, 95% CI=1.092–1.249, P _{heterogeneity}=0.248; GG vs. AA, OR=1.298, 95% CI=1.150–1.465, P _{heterogeneity}<0.001; GG+GA vs. AA, OR=1.087, 95% CI=1.024–1.155, P _{heterogeneity}=0.108; gastric cancer: G allele vs. A allele, OR=1.048, 95% CI=1.010–1.087, P _{heterogeneity}=0.191; hepatocellular carcinoma: G allele vs. A allele, OR=1.105, 95% CI=1.057–1.156, P _{heterogeneity}=0.007; GG vs. AA, OR=1.172, 95% CI=1.105–1.242, P _{heterogeneity}=0.002; GG+GA vs. AA, OR=1.073, 95% CI=1.039–1.108, P _{heterogeneity}=0.111). Given the ethnicity differences in the allele frequency of this sequence variant, we evaluated the effect of EGF +61A/G polymorphism in Asian, European, and mixed populations, respectively. Association of +61A/G polymorphism with increased cancer risk in European population was observed under allelic contrast (OR=1.155, 95% CI=1.018–1.310, P _{heterogeneity}<0.001) and homozygote comparison (OR=1.322, 95% CI=1.028–1.700, P _{heterogeneity}<0.001). Mixed individuals that carried the G allele had an increased cancer risk (G allele vs. A allele, OR=2.015, 95% CI=1.095–3.709, P _{heterogeneity}<0.001; GG vs. AA, OR=3.258, 95% CI=1.220–8.698, P _{heterogeneity}=0.001; GG+GA vs. AA, OR=2.230, 95% CI=1.058–4.701, P _{heterogeneity}=0.006). Summary OR for +61A/G polymorphism stratified by source of control was evaluated, and we also observed an increased association in the allelic contrast (G allele vs. A allele, OR=1.252, 95% CI=1.080–1.451, P _{heterogeneity}<0.001) and in the other two genetic models with HB controls. No significant association was detected between EGF −1380A/G, −1744G/A, and rs6983267 polymorphisms and cancer risk (Table 1).

Table 1.

Stratified Analyses of the Epidermal Growth Factor Polymorphisms and Cancer Risk

			Allelic contrast		Homozygote comparison		Dominant genetic model
Variables	n	Cases/controls	OR (95% CI)	P_h	OR (96% CI)	P_h	OR (98% CI)	P_h
+61A/G
Total	41	9,779/15,932	1.181 (1.077–1.295)	<0.001	1.370 (1.143–1.641)	<0.001	1.175 (1.047–1.318)	<0.001
Cancer type
Breast cancer	2	987/1,154	0.942 (0.726–1.222)	0.042	0.967 (0.903–1.037)	0.013	0.983 (0.954–1.022)	0.046
Cervical cancer	2	435/669	1.022 (0.948–1.101)	0.979	1.025 (0.907–1.159)	0.851	1.024 (0.962–1.090)	0.533
Colorectal cancer	3	441/579	1.144 (1.060–1.235)	0.100	1.293 (1.138–1.469)	<0.001	1.064 (1.000–1.132)	0.119
Esophageal carcinoma	3	779/934	1.168 (1.092–1.249)	0.248	1.298 (1.150–1.465)	<0.001	1.087 (1.024–1.155)	0.108
Gastric cancer	4	1,181/2,324	1.048 (1.010–1.087)	0.191	1.043 (0.995–1.094)	0.443	1.025 (0.998–1.053)	0.889
Glioma	7	1,613/2,267	1.025 (0.836–1.256)	0.001	1.058 (0.692–1.618)	0.001	0.997 (0.969–1.026)	0.029
Hepatocellular carcinoma	6	690/1,933	1.105 (1.057–1.156)	0.007	1.172 (1.105–1.242)	0.002	1.073 (1.039–1.108)	0.111
Lung cancer	2	554/564	1.519 (0.678–3.402)	<0.001	2.344 (0.502–10.940)	0.001	2.054 (0.588–7.177)	0.004
Melanoma	6	2,167/4,211	1.080 (0.889–1.312)	<0.001	1.118 (0.774–1.615)	0.001	1.054 (0.853–1.304)	0.019
Others	6	932/1,297	1.260 (0.763–2.081)	<0.001	1.415 (0.595–3.364)	<0.001	1.106 (0.650–1.880)	<0.001
Ethnicities
Mixed	4	380/1,198	2.015 (1.095–3.709)	<0.001	3.258 (1.220–8.698)	0.001	2.230 (1.058–4.701)	0.006
Asian	19	4,902/6,142	1.102 (0.974–1.248)	<0.001	1.248 (0.958–1.626)	<0.001	1.170 (0.948–1.443)	0.001
European	18	4,497/8,592	1.155 (1.018–1.310)	<0.001	1.322 (1.028–1.700)	<0.001	1.104 (0.973–1.252)	0.004
Sources of controls
PB	15	5,270/9,352	1.087 (0.986–1.200)	<0.001	1.198 (0.979–1.465)	0.001	1.098 (0.965–1.250)	0.068
HB	26	4,509/6,580	1.252 (1.080–1.451)	<0.001	1.504 (1.135–1.992)	<0.001	1.230 (1.028–1.472)	<0.001
−1380A/G
Total	2	1,221/1,314	1.004 (0.980–1.028)	0.222	1.006 (0.987–1.025)	0.735	1.004 (0.990–1.018)	0.599
−1744G/A
Total	2	1,221/1,314	1.006 (0.978–1.034)	0.167	0.999 (0.976–1.022)	0.413	0.998 (0.983–1.013)	0.241
rs6983267
Total	1	110/120	1.985 (1.364–2.889)	-	3.534 (1.635–7.639)	-	1.958 (1.000–3.835)	-

P_h, p-value of Q-test for heterogeneity; in case significant heterogeneity was detected, the random effects model was used; however, the fixed effects model was chosen.

PB, population-based of control group; HB, hospital-based of control group; OR, odds ratio; CI, confidence interval.

Sensitivity analysis

We used sensitivity analysis to evaluate whether modification of the inclusion criteria of the meta-analysis affected the results. We examined the influence of each study on the pooled OR by repeating the analysis while omitting each study one at a time. Moreover, the estimated pooled OR did not change when excluding the studies that were not in HWE.

Discussion

The EGF protein, identified as a potent mitogenic peptide, has multiple biological roles, including proliferation, differentiation, and tumorigenesis of epithelial tissues via interaction with its receptor EGFR (Fisher and Lakshmanan, 1990; Normanno et al., 2001; Harari et al., 2007).

We performed a meta-analysis of association among EGF SNPs (+61, −1380, −1744, and rs6983267) and risk for different types of cancer based on 41 case–control studies. There was significant association between EGF SNP +61A/G and risk of most cancers. Variant genotypes of +61 were associated with a significantly increased cancer risk among both mixed and European populations. Finally, individuals who carried the +61 G allele may have a higher frequency of cancer risk. No association was detected among −1380, −1744, and rs6983267 SNPs and cancer risk. These findings indicate that EGF +61A/G polymorphism may play a critical role in cancer development.

Many studies provided evidence that variant genotypes of EGF were associated with a significantly increased risk for cancer; for example, Teixeira et al. (2008) indicated that carriers of the G-allele had a significantly higher age-adjusted risk for being diagnosed with metastatic prostate cancer and with higher Gleason grade tumors; Hamai et al. (2005) suggested that the A/G polymorphism of EGF was involved not only in the occurrence but also in the malignant progression of gastric cancer. However, it was shown that the GG genotype was not associated with colorectal cancer, gastric cancer, lung cancer, nasopharyngeal carcinoma (Goto et al., 2005; Kang et al., 2007a; Gao et al., 2008; Daraei et al., 2011). Moreover, several studies also found that the variant genotypes of EGF were associated with decreased cancer risk (Araújo et al., 2009b; Bao et al., 2010). To clarify the association between the polymorphisms and cancer risk, we performed a meta-analysis. The results showed that the variant genotypes of +61 were associated with a significantly increased cancer risk for all cancer types. As for cancer type, we found that the variant G allele of EGF +61 was associated with a significantly increased risk for most cancers (colorectal cancer, esophageal carcinoma, gastric cancer, and hepatocellular carcinoma). And we also demonstrated that this SNP does not have an impact on the risk of breast cancer, cervical cancer, glioma, lung cancer, and melanoma. It is not uncommon for the same polymorphism to play different roles in cancer susceptibility across different tumor locations because cancer is an extremely complex disease and genetic heterogeneity exists in different cancer types (Hirschhorn et al., 2002). One important property of the gene polymorphisms is that their incidence can vary substantially among different racial or ethnic populations. In the subgroup analysis by ethnicity, we found that the association among the EGF +61 polymorphism and increased risks of cancer was significant in mixed individuals and Europeans, but not in Asians. Two main reasons can explain this difference: (a) differences in genetic and environmental background exist among different ethnicities; (b) different populations usually have different linkage disequilibrium patterns.

We divided control populations into two parts: HB and PB. In our study, we detected that there was increased association between EGF +61 SNP and cancer risk in HB subgroup. Daraei et al. (2011) found that GG genotype of rs6983267 was a risk factor for the development of sporadic colorectal cancer; in addition, Jin et al. (2007) showed that −1380A/G and −1744G/A may alter plasma EGF levels together with +61A/G, resulting in disturbance of the EGF signaling. However, no relationships were detected in our study. The small sample size could explain this reason.

Some limitations in our meta-analysis should be mentioned. First of all, the number of published studies included in our meta-analysis was not sufficiently large for a comprehensive analysis, especially for −1380A/G, −1744G/A, and rs6983267T/G polymorphisms. Second, the interactions between gene–gene, gene–environment, and even different polymorphic loci of the same gene may modulate cancer risk, so future research and analysis should include these factors. Third, our meta-analysis was based on unadjusted estimates. A more precise analysis could be conducted if individual data were available, which would allow for the adjustment by other covariates including age, sex, family history, environmental factors, cancer stage, and lifestyle. Fourth, the controls were not strictly healthy controls. In summary, our meta-analysis showed evidence that EGF +61A/G polymorphism was associated with significantly increased risk for cancer. Therefore, further well-designed large studies focused on gene–gene and gene–environment interactions are warranted.

Footnotes

Disclosure Statement

No competing financial interests exist.

References

Abu Dayyeh

B.K.

, Yang

, Fuchs

B.C.

, Karl

D.L.

, Yamada

, Sninsky

J.J.

, O'Brien

T.R.

, Dienstag

J.L.

, Tanabe

K.K.

, Chung

R.T.

HALT-C Trial Group. 2011. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology, 141:141–149.

Almeida

L.O.

, Custódio

A.C.

, Santos

M.J.

, Almeida

J.R.

, Clara

C.A.

, Pinto

G.R.

, Rey

J.A.

, Casartelli

2010. The A61G EGF polymorphism is associated with development of extraaxial nervous system tumors but not with overall survival. Cancer Genet Cytogenet, 198:15–21.

Amend

K.L.

, Elder

J.T.

, Tomsho

L.P.

, Bonner

J.D.

, Johnson

T.M.

, Schwartz

, Berwick

, Gruber

S.B.

2004. EGF gene polymorphism and the risk of incident primary melanoma. Cancer Res, 64:2668–2672.

Araújo

A.P.

, Catarino

, Ribeiro

, Pereira

, Pinto

, Medeiros

2011a. Epidermal growth factor genetic variation associated with advanced cervical cancer in younger women. Am J Clin Oncol[Epub ahead of print]10.1097/COC.0b013e31820dbbf5.

Araújo

A.P.

, Costa

B.M.

, Pinto-Correia

A.L.

, Fragoso

, Ferreira

, Dinis-Ribeiro

, Costa

, Reis

R.M.

, Medeiros

2011b. Association between EGF +61A/G polymorphism and gastric cancer in Caucasians. World J Gastroenterol, 17:488–492.

Araújo

A.P.

, Ribeiro

, Pereira

, Pinto

, Sousa

, Catarino

, Medeiros

2009a. Ovarian cancer and genetic susceptibility: association of A61G polymorphism in the EGF gene. Exp Biol Med (Maywood), 234:241–245.

Araújo

A.P.

, Ribeiro

, Pinto

, Pereira

, Sousa

, Mauricio

, Lopes

, Medeiros

2009b. Epidermal growth factor genetic variation, breast cancer risk, and waiting time to onset of disease. DNA Cell Biol, 28:265–269.

Bao

, Wang

, Guo

, Han

, Xu

2010. Association between epidermal growth factor +61 G/A polymorphism and glioma risk in a Chinese Han population. J Int Med Res, 38:1645–1652.

Bhowmick

D.A.

, Zhuang

, Wait

S.D.

, Weil

R.J.

2004. A functional polymorphism in the EGF gene is found with increased frequency in glioblastoma multiforme patients and is associated with more aggressive disease. Cancer Res, 64:1220–1223.

10.

Casula

, Alaibac

, Pizzichetta

M.A.

, Bono

, Ascierto

P.A.

, Stanganelli

, Canzanella

, Palomba

, Zattra

Italian Melanoma Intergroup (IMI). Palmieri

2009. Role of the EGF +61A>G polymorphism in melanoma pathogenesis: an experience on a large series of Italian cases and controls. BMC Dermatol, 9:7.

11.

Chen

, Wei

, Yang

, Li

2011. Epidermal growth factor +61 G/A polymorphism and the risk of hepatocellular carcinoma in a Chinese population. Genet Test Mol Biomarkers, 15:251–255.

12.

Chen

Y.F.

, Qi

, Ruan

C.P.

, Wang

, Xu

X.J.

, Sun

X.J.

, Liu

, Gao

C.F.

2009. Relationship between polymorphism of epidermal growth factor 5′UTR variant G61A gene and colorectal in patients in China. Pract J Cancer, 24:551–554.

13.

Cheung

W.Y.

, Zhai

, Kulke

M.H.

, Heist

R.S.

, Asomaning

, Ma

, Wang

, Su

, Lanuti

, Tanabe

K.K.

, Christiani

D.C.

, Liu

2009. Epidermal growth factor A61G gene polymorphism, gastroesophageal reflux disease and esophageal adenocarcinoma risk. Carcinogenesis, 30:1363–1367.

14.

Costa

B.M.

, Ferreira

, Costa

, Canedo

, Oliveira

, Silva

, Pardal

, Suriano

, Machado

J.C.

, Lopes

J.M.

, Reis

R.M.

2007. Association between functional EGF +61 polymorphism and glioma risk. Clin Cancer Res, 13:2621–2626.

15.

Cui

, Pan

X.M.

, Ma

C.F.

, Shang-Guan

, Yu

H.B.

, Chen

G.X.

, Wang

2010. Association between epidermal growth factor polymorphism and esophageal squamous cell carcinoma susceptibility. Dig Dis Sci, 55:40–45.

16.

Daraei

, Salehi

, Emami

M.H.

, Janghorbani

, Mohamadhashem

, Tavakoli

2011. Erratum to: effect of rs6983267 polymorphism in the 8q24 region and rs4444903 polymorphism in EGF gene on the risk of sporadic colorectal cancer in Iranian population. Med Oncol[Epub ahead of print]10.1007/s12032-011-9980-2.

17.

DerSimonian

, Laird

1986. Meta-analysis in clinical trials. Control Clin Trials, 7:177–188.

18.

Dong

L.M.

, Potter

J.D.

, White

, Ulrich

C.M.

, Cardon

L.R.

, Peters

2008. Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA, 299:2423–2436.

19.

Fisher

D.A.

, Lakshmanan

1990. Metabolism and effects of epidermal growth factor and related growth factors in mammals. Endocr Rev, 11:418–442.

20.

Gao

L.B.

, Wei

Y.S.

, Zhou

, Wang

Y.Y.

, Liang

W.B.

, Li

, Bai

, Fang

W.L.

, Xue

, Zhang

2008. No association between epidermal growth factor and epidermal growth factor receptor polymorphisms and nasopharyngeal carcinoma. Cancer Genet Cytogenet, 185:69–73.

21.

Goto

, Ando

, Goto

, Hamajima

2005. No association between EGF gene polymorphism and gastric cancer. Cancer Epidemiol Biomarkers Prev, 14:2454–2456.

22.

Hamai

, Matsumura

, Matsusaki

, Kitadai

, Yoshida

, Yamaguchi

, Imai

, Nakachi

, Toge

, Yasui

2005. A single nucleotide polymorphism in the 5′ untranslated region of the EGF gene is associated with occurrence and malignant progression of gastric cancer. Pathobiology, 72:133–138.

23.

Harari

P.M.

, Allen

G.W.

, Bonner

J.A.

2007. Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol, 25:4057–4065.

24.

Harismendy

, Frazer

K.A.

2009. Elucidating the role of 8q24 in colorectal cancer. Nat Genet, 41:868–869.

25.

Hirschhorn

J.N.

, Lohmueller

, Byrne

, Hirschhorn

2002. A comprehensive review of genetic association studies. Genet Med, 4:45–61.

26.

James

M.R.

, Hayward

N.K.

, Dumenil

, Montgomery

G.W.

, Martin

N.G.

, Duffy

D.L.

2004. Epidermal growth factor gene (EGF) polymorphism and risk of melanocytic neoplasia. J Invest Dermatol, 123:760–762.

27.

Jemal

, Bray

, Center

M.M.

, Ferlay

, Ward

, Forman

2011. Global cancer statistics. CA Cancer J Clin, 61:69–90.

28.

Jin

, Miao

, Deng

, Hu

, Zhou

, Tan

, Wang

, Hua

, Ding

, Wang

, Chen

, Shen

, Wang

, Xu

, Shen

2007. 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, 98:864–868.

29.

Jorissen

R.N.

, Walker

, Pouliot

, Garrett

T.P.

, Ward

C.W.

, Burgess

A.W.

2003. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res, 284:31–53.

30.

Kang

H.G.

, Choi

J.E.

, Lee

W.K.

, Kam

, Cha

S.I.

, Kim

C.H.

, Jung

T.H.

, Park

J.Y.

2007a. +61A>G polymorphism in the EGF gene does not increase the risk of lung cancer. Respirology, 12:902–905.

31.

Kang

, Kim

J.W.

, Park

N.H.

, Song

Y.S.

, Park

S.Y.

, Kang

S.B.

, Lee

H.P.

2007b. Epidermal growth factor 61 A/G polymorphism and uterine cervical cancer. Int J Gynecol Cancer, 17:492–496.

32.

Lanuti

, Liu

, Goodwin

J.M.

, Zhai

, Fuchs

B.C.

, Asomaning

, Su

, Nishioka

N.S.

, Tanabe

K.K.

, Christiani

D.C.

2008. A functional epidermal growth factor (EGF) polymorphism, EGF serum levels, and esophageal adenocarcinoma risk and outcome. Clin Cancer Res, 14:3216–3222.

33.

, Xie

, Lu

, Zhao

, Mao

, Li

, Liu

, Zhuang

2010. Association between epidermal growth factor 61A/G polymorphism and hepatocellular carcinoma susceptibility in Chinese patients. Liver Int, 30:112–118.

34.

Lim

Y.J.

, Kim

J.W.

, Song

J.Y.

, Hong

M.S.

, Jin

S.Y.

, Yoon

S.H.

, Park

H.J.

, Choe

B.K.

, Lee

J.J.

, Yim

S.V.

, Hong

S.I.

, Baik

H.H.

, Ha

, Park

Y.H.

2005. Epidermal growth factor gene polymorphism is different between schizophrenia and lung cancer patients in Korean population. Neurosci Lett, 374:157–160.

35.

Limaye

P.B.

, Bowen

W.C.

, Orr

A.V.

, Luo

, Tseng

G.C.

, Michalopoulos

G.K.

2008. Mechanisms of hepatocyte growth factor-mediated and epidermal growth factor-mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium. Hepatology, 47:1702–1713.

36.

Liu

, Li

, Chen

, Wang

, Mu

, Li

, Xu

, Xie

, Lu

2009. No association between EGF +61 A/G polymorphism and increased risk of glioma. Int J Biol Markers, 24:77–82.

37.

Mantel

, Haenszel

1959. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22:719–748.

38.

McCarron

S.L.

, Bateman

A.C.

, Theaker

J.M.

, Howell

W.M.

2003. EGF +61 gene polymorphism and susceptibility to and prognostic markers in cutaneous malignant melanoma. Int J Cancer, 107:673–675.

39.

Normanno

, Bianco

, De Luca

, Salomon

D.S.

2001. The role of EGF-related peptides in tumor growth. Front Biosci, 6:D685–D707.

40.

Normanno

, De Luca

, Bianco

, Strizzi

, Mancino

, Maiello

M.R.

, Carotenuto

, De Feo

, Caponigro

, Salomon

D.S.

2006. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 366:2–16.

41.

Pinto

G.R.

, Yoshioka

F.K.

, Clara

C.A.

, Santos

M.J.

, Almeida

J.R.

, Burbano

R.R.

, Rey

J.A.

, Casartelli

2009. Association study of an epidermal growth factor gene functional polymorphism with the risk and prognosis of gliomas in Brazil. Int J Biol Markers, 24:277–281.

42.

, Chen

Y.M.

, Gao

C.F.

, Fang

, Sun

X.J.

, Liu

2008. Relationship between polymorphism of epidermal growth factor 5′UTR variant G61A gene and hepatocellular carcinoma in patients with chronic hepatitis B virus infection in China. Chin J Biol, 21:1051–1053.

43.

, Wang

, Chen

Y.M.

, Sun

X.J.

, Liu

, Gao

C.F.

2009. No association of EGF 5′UTR variant A61G and hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. Pathology, 41:555–560.

44.

Randerson-Moor

J.A.

, Gaut

, Turner

, Whitaker

, Barrett

J.H.

, Silva Idos

, Swerdlow

, Bishop

D.T.

, Bishop

J.A.

2004. The relationship between the epidermal growth factor (EGF) 5′UTR variant A61G and melanoma/nevus susceptibility. J Invest Dermatol, 123:755–759.

45.

Shahbazi

, Pravica

, Nasreen

, Fakhoury

, Fryer

A.A.

, Strange

R.C.

, Hutchinson

P.E.

, Osborne

J.E.

, Lear

J.T.

, Smith

A.G.

, Hutchinson

I.V.

2002. Association between functional polymorphism in EGF gene and malignant melanoma. Lancet, 359:397–401.

46.

Tanabe

K.K.

, Lemoine

, Finkelstein

D.M.

, Kawasaki

, Fujii

, Chung

R.T.

, Lauwers

G.Y.

, Kulu

, Muzikansky

, Kuruppu

, Lanuti

, Goodwin

J.M.

, Azoulay

, Fuchs

B.C.

2008. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA, 299:53–60.

47.

Teixeira

A.L.

, Ribeiro

, Cardoso

, Pinto

, Lobo

, Fraga

, Pina

, Calais-da-Silva

, Medeiros

2008. Genetic polymorphism in EGF is associated with prostate cancer aggressiveness and progression-free interval in androgen blockade-treated patients. Clin Cancer Res, 14:3367–3371.

48.

Vauleon

, Auger

, Benouaich-Amiel

, Laigle-Donadey

, Kaloshi

, Lejeune

, Delattre

J.Y.

, Thillet

, Sanson

2007. The 61 A/G EGF polymorphism is functional but is neither a prognostic marker nor a risk factor for glioblastoma. Cancer Genet Cytogenet, 172:33–37.

49.

Vishnoi

, Pandey

S.N.

, Modi

D.R.

, Kumar

, Mittal

2008. Genetic susceptibility of epidermal growth factor +61A>G and transforming growth factor beta1-509C>T gene polymorphisms with gallbladder cancer. Hum Immunol, 69:360–367.

50.

Wang

, Zhao

, Ruan

, Chen

, Fan

, Chen

, Wu

, Qian

, Zhang

, Huang

, Lu

2010. Association between EGF +61 G/A and glioma risk in a Chinese population. BMC Cancer, 10:221.

51.

Wang

, Tian

, Hu

, Tang

, Wang

, Qin

, Huo

, Gao

, Ke

, Jin

, Ma

, Wang

, Shen

2008. EGF promoter SNPs, plasma EGF levels and risk of breast cancer in Chinese women. Breast Cancer Res Treat, 111:321–327.

52.

Wokolorczyk

, Gliniewicz

, Sikorski

, Zlowocka

, Masojc

, Debniak

, Matyjasik

, Mierzejewski

, Medrek

, Oszutowska

, Suchy

, Gronwald

, Teodorczyk

, Huzarski

, Byrski

, Jakubowska

, Górski

, van de Wetering

, Walczak

, Narod

S.A.

, Lubinski

, Cybulski

2008. A range of cancers is associated with the rs6983267 marker on chromosome 8. Cancer Res, 68:9982–9986.

53.

World Health Organization. 2008. The Global Burden of Disease: 2004 Update. World Health Organization: Geneva.

54.

G.Y.

, Hasenberg

, Magdeburg

, Bönninghoff

, Sturm

J.W.

, Keese

2009. Association between EGF, TGF-beta1, VEGF gene polymorphism and colorectal cancer. World J Surg, 33:124–129.

55.

G.Y.

, Lu

, Hasenberg

, Niedergethmann

, Post

, Sturm

J.W.

, Keese

2010. Association between EGF, TGF-{beta}1, TNF-{alpha} gene polymorphisms and cancer of the pancreatic head. Anticancer Res, 30:5257–5261.

56.

Yuan

, Yin

C.J.

, Zhao

, Qin

, Zhang

Z.D.

, Zhang

2011. The association between the −61G>A polymorphism in the epidermal growth factor gene and susceptibility to renal clear cell carcinoma. Chin J Exp Surg, 28:108–111.

57.

Zintzaras

2010. The generalized odds ratio as a measure of genetic risk effect in the analysis and meta-analysis of association studies. Stat Appl Genet Mol Biol, 9Article21.