Mutations of the core gene sequence of HCV from patients with hepatocellular carcinoma in China and Japan

首先，我们调查了肝细胞癌（HCC）和丙型肝炎病毒（HCV）分离的基因组特征的长江沿岸地区的居民之间的关联。该地区是中国HCC发病率最高的地区之一，我们的数据显示，核苷酸替换不均匀地沿着分布在HCV基因组中，在编码核心蛋白第二亲水结构域的区域中存在一簇错义突变，并且在来自HCC患者的分离株中，这些突变在聚集可变区（CVR）中的数量显著高于来自慢性肝炎个体的分离株。其次，我们确定了日本HCC患者癌性和非癌性肝组织中HCV分离株的CVR序列差异，肝组织中引起CVR氨基酸残基变化的核苷酸替换数量显著高于HCC患者血清。在每个患者中，与来自癌性肝部分的代表性克隆不同的CVR中的氨基酸残基的数目显著高于与非癌性部分不同的数目。CVR中核心密码子45处的氨基酸从Gly到Ser的改变在非癌部分而不是癌部分和HCC患者血清中占主导地位。这些发现表明，大量突变，包括来自肝组织的HCV核心基因中具有生物学重要性的氨基酸序列变化，可能与肝癌发生有关。

Firstly, we investigated the association between hepatocellular carcinoma(HCC)and the genomic characteristics of the hepatitis C virus(HCV)isolated from residents of the inshore region of the Yangtze River. That area of China has one of the highest incidences of HCC.Our data revealed that nucleotide substitutions are unevenly scattered along the HCV genome, with a cluster of missense mutations in the region encoding the second hydrophilic domain of the core protein, and that the number of these mutations in the clustering variable region(CVR)is significantly higher in isolates from HCC patients than in those from individuals with chronic hepatitis. Secondly, we determined the sequence divergence of the CVR in HCV isolates from cancerous and noncancerous liver tissues in Japanese patients with HCC.The number of nucleotide substitutions giving rise to changes in amino acid residues in the CVR was significantly greater in liver tissues than in sera from HCC patients. The number of amino acid residues in the CVR that differed from the representative clone from cancerous liver portions was significantly higher than the number differing from noncancerous portions in each patient. An amino acid alteration from Gly to Ser at core codon 45 in the CVR was dominant in noncancerous portions rather than in cancerous portions and sera from HCC patients. These findings suggest that a large number of mutations, including biologically important amino acid sequence changes in the HCV core gene from liver tissue, might be related to hepatocarcinogenesis.