Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas
Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas
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DOI：
10.1038/ng.3389
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发表时间：
2015-10-01
期刊：
影响因子：
30.8
通讯作者：
Zucman-Rossi, Jessica
中科院分区：
文献类型：
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作者：
Nault, Jean-Charles;Datta, Shalini;Zucman-Rossi, Jessica
肝细胞癌（HCC）是与各种病因相关的肝脏肿瘤，包括酒精摄入和B型肝炎（HBV）或C型肝炎（HCV）病毒感染。其他危险因素仍有待确定，特别是在没有肝硬化的HCC患者中。我们发现克隆整合的腺相关病毒2型（AAV 2）在193 HCC的11。这些AAV 2整合发生在已知的癌症驱动基因中，即CCNA 2（细胞周期蛋白A2; 4例）、TERT（端粒酶逆转录酶; 1例）、CCNE 1（细胞周期蛋白E1; 3例）、TNFSF 10（肿瘤坏死因子超家族成员10; 2例）和KMT 2B（赖氨酸特异性甲基转移酶2B; 1例），导致靶基因的过表达。具有病毒整合的肿瘤主要在非炎性肝脏中发展（11例中的9例）并且没有已知的风险因素（11例中的6例），这表明AAV 2在这些患者中的致病作用。总之，AAV 2是与人HCC中的致癌插入突变相关的DNA病毒。
Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.