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

首先，我们研究了从长江沿岸地区居民中分离的丙型肝炎病毒（HCV）基因组特征与肝细胞癌（HCC）之间的关系。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分散在HCV基因组中，在编码核心蛋白的第二个亲水结构域的区域存在一簇错义突变，并且HCC患者分离物中聚类可变区（CVR）的这些突变数量明显高于慢性肝炎患者分离物。其次，我们确定了日本HCC患者癌性和非癌性肝组织HCV分离株CVR的序列差异。肝组织中引起CVR中氨基酸残基改变的核苷酸取代数量明显大于HCC患者血清。在每个患者中，CVR中与癌变肝脏部分的代表性克隆不同的氨基酸残基数量显著高于与非癌变肝脏部分不同的氨基酸残基数量。CVR核心密码子45上从Gly到Ser的氨基酸改变在HCC患者的非癌性部分和血清中占主导地位，而在癌性部分和血清中占主导地位。这些发现表明，大量的突变，包括肝组织中HCV核心基因中重要的氨基酸序列变化，可能与肝癌的发生有关。

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.