表皮生長因子基因多型性和B型肝炎帶原者之肝細胞癌危險性：世代研究

Abstract

背景：表皮生長因子（EGF）所調控的訊號傳遞影響各種細胞的生長、分化，位在 此基因上的基因多型性可能在上皮細胞癌，例如肝細胞癌的發展佔有重要的地位。方法：本研究選擇了兩個在表皮生長因子基因上的功能性SNP 做分析，分別為5’UTR 上的rs4444903 及exon 15 上的rs11569017。世代研究包括4432 個B 型肝炎帶原男性，分別從公務人員健康檢查及林口長庚紀念醫院在1989 到1992 之間進入，至2007 年約追蹤16 年且已有200 個肝細胞癌病例。本研究也利用長期追蹤病毒量資料、B 型肝炎病毒基因型及B 型肝炎e 抗原狀態等病毒因子來評估B型肝炎病毒對於SNPs 及肝細胞癌之間的關係的影響（n=1133）。結果：本研究沒有發現兩個SNP 與肝細胞癌或肝硬化之間有任何相關；但在SNP rs4444903 與B 型肝炎病毒量之間發現有負相關，無論是單點資料或是長期追蹤資料都達到顯著，多變項調整之勝算比分別為：單點資料AG vs AA= 0.56 （95%信賴區間：0.35-0.91）；GG vs AA= 0.54（信賴區間：0.33-0.86），長期追蹤資料：AG vs AA= 0.68（95%信賴區間：0.56-0.83）; GG vs AA= 0.67（95%信賴區間：0.56-0.82）。 結論：本研究的結果無法證實SNP rs4444903 對上皮細胞癌的發生的影響，但就結果顯現該SNP 可能在B 型肝炎帶原者身上對病毒的複製活性有影響。此部份需要更詳盡的研究，對於未來B 型肝炎帶原者病情的監控以及接受相關的治療應該會有很大的幫助。

Background: The epidermal growth factor (EGF) signaling pathway affects cell proliferation and differentiation. Polymorphism in the EGF gene may play a role in the development of epithelial cancers, such as hepatocellular carcinoma (HCC). Methods: We genotyped two EGF functional polymorphisms (rs4444903 at 5’ untranslated region [UTR] and rs11569017 at exon 15) in a cohort of 4432 cancer-free HBsAg-positive men (of whom 200 developed HCC and 4232 remained unaffected through 16 years of follow-up) who were recruited from Government Employee Central Clinics and Chang Gung Memorial Hospital between 1989 and 1992. To evaluate the impact of HBV viral factors on the association between the EGF SNPs and HCC, a longitudinal viral-load study (n=1133) with available data on HBeAg status and HBV genotype and DNA were also conducted within the cohort study. Results: We did not observe any association with the two EGF SNPs for HCC or cirrhosis. However, a statistically, significantly inverse association was found between SNP rs4444903 and circulating HBV DNA level, irrespective of cross-sectional (adjusted odds ratio [95% confidence interval]: AG vs AA= 0.56 [95% CI=0.35-0.91]; GG vs AA= 0.54 [95% CI=0.33-0.86]) or longitudinal (adjusted odds ratio [95% confidence interval]: AG vs AA= 0.68 [95% CI=0.56-0.83]; GG vs AA= 0.67 [95% CI=0.56-0.82]) measure of viral load. Conclusion: Our results argue against a role of the EGF 5’ UTR SNP in epithelial cancers. EGF genetic polymorphism may alter viral replication activity during the development of HCC among HBsAg carriers. A better understanding of the relationship between the EGF 5’ UTR SNP and viral load might be valuable for monitoring HBsAg carriers with HCC under treatment with inhibitors of EGF signaling pathway.