A Functional Polymorphism in the Epidermal Growth Factor Gene Is Associated With Risk for Hepatocellular Carcinoma

Abstract

Background & Aims A single nucleotide polymorphism 61*G (rs4444903) in the Epidermal Growth Factor (EGF) gene has been associated, in 2 case-control studies, with hepatocellular carcinoma (HCC). We tested associations between demographic, clinical, and genetic data and development of HCC, and developed a simple predictive model in a cohort of patients with chronic hepatitis C and advanced fibrosis. Methods Black and white subjects from the HALT-C trial (n=816) were followed prospectively for development of a definite or presumed case of HCC for a median time period of 6.1 years. We used the Cox proportional hazards regression model to determine the hazard ratio for risk of HCC and to develop prediction models. Results Subjects with EGF genotype G/G had a higher adjusted risk for HCC than those with genotype A/A (hazard ratio, 2.10; 95% confidence interval, 1.05–4.23; P=0.03). After adjusting for EGF genotype, blacks had no increased risk of HCC risk, compared with whites. Higher serum levels of EGF were observed among subjects with at least one G allele (P=0.08); the subset of subjects with EGF G/G genotype and above-median serum levels of EGF had the highest risk of HCC. We developed a simple prediction model that included the EGF genotype to identify patients at low, intermediate, and high risk for HCC; 6-year cumulative HCC incidences were 2.3%, 10.4%, and 26%, respectively. Conclusions We associated the EGF genotype G/G with increased risk for HCC; differences in its frequency among black and white subjects might account for differences in HCC incidence between these groups. We developed a model that incorporates EGF genotype and demographic and clinical variables to identify patients at low, intermediate, and high risk for HCC.

Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

“…The finding that the EGFR/ MEK pathway promotes aberrant IR-A splicing in HCC cells makes logical sense in relation to cellular transformation as this pathway is frequently dysregulated in human HCC (28) and participates in liver carcinogenesis in animal models (24,35). Consistently, high serum levels of EGF are associated with increased HCC risk in patients with cirrhosis (36,37). EGFR ligands are overproduced by HCC tumors and also by cells from tumor environment such as cirrhotic hepatocytes, hepatic fibroblasts, and inflammatory cells (29,(38)(39)(40).…”

Quantitative assessment of the effect of epidermal growth factor 61A/G polymorphism on the risk of hepatocellular carcinoma

“…Overall, 2,095 patients with HCC and 3,766 control individuals were retrieved. Seven of the studies enrolled Chinese individuals (15,(22)(23)(24)(25)(26), three studies involved a mixed population, including Caucasian, Hispanic and Asian populations and individuals of African descent (21,22,27), one study enrolled only Caucasians (21) and one enrolled only Egyptian individuals (28). The genotype distributions in the controls for all studies were consistent with the HWE expectations.…”

“…The publications by Zhong et al (15), Tanabe et al (21) and Yuan et al (22) all involved two independent case-control studies and were overall considered to be six single studies. Finally, a total of 12 studies (15,(21)(22)(23)(24)(25)(26)(27)(28) that examined the association between the EGF 61A/G polymorphism and the risk of HCC were included in the current meta-analysis (Fig. 1).…”

Association of Epidermal Growth Factor and Epidermal Growth Factor Receptor Polymorphisms with the Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma in the Population of North China

“…The EGFR in the tumor endothelial cells may play a role for tumor angiogenesis in HCC via paracrine mechanisms (Moon et al, 2006), and apparent EGF overexpression is detected in the serum of HCC patients (Abu Dayyeh et al, 2011), both demonstrate that the EGF and EGFR play an important role in the process of tumorigenesis. Yoneda et al (2011) performed the experiment to investigate the mechanism underlying the development of cytokeratin19-positive HCC, the results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of cytokeratin 19-positive HCC, and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients.…”