Comprehensive mapping of the human papillomavirus (HPV) DNA integration sites in cervical carcinomas by HPV capture technology.
Comprehensive mapping of the human papillomavirus (HPV) DNA integration sites in cervical carcinomas by HPV capture technology.
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DOI：
10.18632/oncotarget.6809
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发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Ke Y
中科院分区：
文献类型：
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作者：
Liu Y;Lu Z;Xu R;Ke Y
人类乳头瘤病毒(HPV)DNA整合到宿主基因组中可能是宫颈癌的驱动突变。在碱基分辨下识别HPV整合一直是一个长期的技术挑战，这主要是由于HPV在内切体或串联形式中掩盖了敏感性。目的是利用创新战略提高对HPV整合部位精确本地化的理解。应用HPV捕获技术结合下一代测序技术，对47例宫颈癌组织和2株细胞株进行了HPV感染情况和HPV DNA整合位点的检测。共鉴定出117个独特的HPV整合位点，包括HPV16(n=101)、HPV18(n=7)和HPV58(n=9)。我们观察到HPV16整合位点广泛分布于整个病毒基因组。此外，HPV16的单个或多个整合事件可能频繁发生，每个样本从1到19个不等。病毒整合位点几乎分布在除22号染色体以外的所有染色体上。HPV16整合位点在4个以上的宫颈癌均为临床诊断为III期癌。在整合断裂点观察到人类基因组和HPV基因组之间共享的重叠核苷酸显著丰富，表明它可能在HPV整合过程中发挥重要作用。这些结果扩展了先前关于HPV16和HPV18整合位点的知识，并使人们能够更好地理解宫颈癌发病的分子基础。
Integration of human papillomavirus (HPV) DNA into the host genome can be a driver mutation in cervical carcinoma. Identification of HPV integration at base resolution has been a longstanding technical challenge, largely due to sensitivity masking by HPV in episomes or concatenated forms. The aim was to enhance the understanding of the precise localization of HPV integration sites using an innovative strategy. Using HPV capture technology combined with next generation sequencing, HPV prevalence and the exact integration sites of the HPV DNA in 47 primary cervical cancer samples and 2 cell lines were investigated. A total of 117 unique HPV integration sites were identified, including HPV16 (n = 101), HPV18 (n = 7), and HPV58 (n = 9). We observed that the HPV16 integration sites were broadly located across the whole viral genome. In addition, either single or multiple integration events could occur frequently for HPV16, ranging from 1 to 19 per sample. The viral integration sites were distributed across almost all the chromosomes, except chromosome 22. All the cervical cancer cases harboring more than four HPV16 integration sites showed clinical diagnosis of stage III carcinoma. A significant enrichment of overlapping nucleotides shared between the human genome and HPV genome at integration breakpoints was observed, indicating that it may play an important role in the HPV integration process. The results expand on knowledge from previous findings on HPV16 and HPV18 integration sites and allow a better understanding of the molecular basis of the pathogenesis of cervical carcinoma.