Hypermutation in the E2 gene of human papillomavirus type 16 in cervical intraepithelial neoplasia
Hypermutation in the E2 gene of human papillomavirus type 16 in cervical intraepithelial neoplasia
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DOI：
10.1002/jmv.24215
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发表时间：
2015-10-01
影响因子：
12.7
通讯作者：
Kondo, Kazunari
中科院分区：
文献类型：
--
作者：
Kukimoto, Iwao;Mori, Seiichiro;Kondo, Kazunari
人乳头瘤病毒（HPV）感染是导致宫颈癌的主要原因。然而，宫颈癌发生过程中的病毒遗传变化尚未完全了解。最近的研究表明，在宫颈上皮内瘤变（CIN）病变中，HPV 16基因组长控制区存在腺嘌呤/胸腺嘧啶簇状超突变，并表明载脂蛋白B mRNA编辑酶，催化多肽样（APOBEC）蛋白，在抗逆转录病毒感染的先天免疫中起关键作用，可能引入这种超突变。本研究报告首次检测到腺嘌呤/胸腺嘧啶聚集性高突变的E2基因的HPV 16分离自临床标本与低，高级别CIN病变（CIN 1/3）。差异DNA变性PCR，利用较低的变性温度，选择性地扩增腺嘌呤/胸腺嘧啶丰富的DNA，确定在E2基因中的腺嘌呤/胸腺嘧啶突变簇在4的11个CIN 1（36.4%），和6的27个CIN 3（22.2%）的样品。有趣的是，每个样本的突变数量在CIN 3中高于CIN 1。虽然E2超突变在宫颈癌发生中的相关性尚不清楚，但观察到的超突变模式强烈暗示APOBEC 3蛋白在自然病毒感染期间参与编辑HPV 16基因组。J. Med. Virol. 87：1754-1760，2015. (c)2015 Wiley Periodicals，Inc.
Persistent infection with oncogenic human papillomavirus (HPV) causes cervical cancer. However, viral genetic changes during cervical carcinogenesis are not fully understood. Recent studies have revealed the presence of adenine/thymine-clustered hypermutation in the long control region of the HPV16 genome in cervical intraepithelial neoplasia (CIN) lesions, and suggested that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins, which play a key role in innate immunity against retroviral infection, potentially introduce such hypermutation. This study reports for the first time the detection of adenine/thymine-clustered hypermutation in the E2 gene of HPV16 isolated from clinical specimens with low- and high-grade CIN lesions (CIN1/3). Differential DNA denaturation PCR, which utilizes lower denaturation temperatures to selectively amplify adenine/thymine-rich DNA, identified clusters of adenine/thymine mutations in the E2 gene in 4 of 11 CIN1 (36.4%), and 6 of 27 CIN3 (22.2%) samples. Interestingly, the number of mutations per sample was higher in CIN3 than in CIN1. Although the relevance of E2 hypermutation in cervical carcinogenesis remains unclear, the observed hypermutation patterns strongly imply involvement of APOBEC3 proteins in editing the HPV16 genome during natural viral infection. J. Med. Virol. 87:1754-1760, 2015. (c) 2015 Wiley Periodicals, Inc.