A functional polymorphism in the epidermal growth factor gene predicts hepatocellular carcinoma risk in Japanese hepatitis C patients

Abstract

Masaya Suenaga,1 Suguru Yamada,1 Tsutomu Fujii,1 Bryan C Fuchs,2 Norio Okumura,1 Mitsuro Kanda,1 Daisuke Kobayashi,1 Chie Tanaka,1 Goro Nakayama,1 Hiroyuki Sugimoto,1 Masahiko Koike,1 Shuji Nomoto,1 Michitaka Fujiwara,1 Shin Takeda,3 Kazuhiko Hayashi,4 Kenneth K Tanabe,2 Hidemi Goto,4 Yasuhiro Kodera11Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan; 2Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA; 3Division of Surgery, Nagoya Medical Center, Nagoya, Japan; 4Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, JapanBackground: A single nucleotide polymorphism (SNP) in the epidermal growth factor (EGF) gene (rs4444903) has been associated with increased risk of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the relationship between the EGF SNP genotype and the development and prognosis of HCC, in a Japanese population.Methods: Restriction fragment-length polymorphism was used to determine the presence of the EGF SNP genotype in 498 patients, including 208 patients with HCC. The level of EGF messenger ribonucleic acid (mRNA) expression in cancerous tissues was measured by quantitative reverse transcription polymerase chain reaction. The correlation between the EGF SNP genotype and prognosis was statistically analyzed in the patients with HCC.Results: The proportion of the A/A, A/G, and G/G genotypes were 5.3%, 42.8%, and 51.9%, respectively, in the patients with HCC, whereas in those without HCC, they were 8.6%, 35.9%, and 55.5%, respectively, revealing that the odds ratio (OR) of developing HCC was higher in patients with a G allele (OR =1.94, P=0.080 for A/G patients and OR =1.52, P=0.261 for G/G patients, as compared with A/A patients). In particular, when the analysis was limited to the 363 patients with hepatitis C, the OR for developing HCC was 3.54 (P=0.014) for A/G patients and was 2.85 (P =0.042) for G/G patients, as compared with A/A patients. Tumoral EGF mRNA expression in G/G patients was significantly higher than that in A/A patients (P=0.033). No statistically significant differences were observed between the EGF SNP genotype and disease-free or overall survival.Conclusion: The EGF SNP genotype might be associated with a risk for the development of HCC in Japanese patients but not with prognosis. Of note, the association is significantly stronger in patients with hepatitis C, which is the main risk factor for HCC in Japan.Keywords: epidermal growth factor, functional polymorphism, hepatocellular carcinoma, hepatitis C, hepatocarcinogenesis