Type-dependent integration frequency of human papillomavirus genomes in cervical lesions
Type-dependent integration frequency of human papillomavirus genomes in cervical lesions
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DOI：
10.1158/0008-5472.can-07-2754
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Doeberitz, Magnus von Knebel
中科院分区：
文献类型：
--
作者：
Vinokurova, Svetlana;Wentzensen, Nicolas;Doeberitz, Magnus von Knebel
高危型人乳头瘤病毒（HR-HPV）基因组的染色体整合被认为是宫颈癌发病机制中的一个重要事件，与癌前病变向浸润性癌的进展有关。这一假设是基于实验数据，表明HR-HPV E2基因功能的整合依赖性破坏对实现肿瘤转化很重要，并基于通过分析人乳头瘤病毒（HPV）16和18诱导的病变收集的临床数据，这些数据显示绝大多数宫颈癌细胞中存在整合的病毒基因组拷贝。然而，相当一部分宫颈癌与其他HR-HPV类型相关，迄今为止几乎没有关于其整合状态的数据报道。在这里，我们比较了五种最常见的致癌HPV类型（HPV 16，18，31，33和45）的整合频率在一系列的835宫颈样本使用特定的mRNA为基础的PCR检测（扩增乳头瘤病毒癌基因转录）。大多数癌前病变显示完全游离型病毒基因组，而62%的癌病毒基因组整合。然而，整合HR-HPV基因组的频率显示出个体HR-HPV类型的显著差异。与HPV 31和33型相比，HPV 16、18和45在整合状态下更常见。对高级别癌前病变和浸润性癌症患者的中位年龄分析表明，与HPV 31和33型诱导的癌前病变相比，HPV 18、16和45型诱导的癌前病变进展为浸润性宫颈癌的时间要短得多。这些发现表明，致癌HPV基因组在宫颈病变中的整合是由HR-HPV E6-E7癌基因表达失调诱导的染色体不稳定的结果，而不是原因。不同的HR-HPV类型显然在其宿主细胞中引起染色体不稳定性，其程度与其在晚期病变中的整合频率和CIN 3病变进展为浸润性癌症所需的时间所反映的不同。
Chromosomal integration of high-risk human papillomavirus (HR-HPV) genomes is believed to represent a significant event in the pathogenesis of cervical cancer associated with progression from preneoplastic lesions to invasive carcinomas. This hypothesis is based on experimental data suggesting that integration-dependent disruption of HR-HPV E2 gene functions is important to achieve neoplastic transformation and on clinical data gathered by analyzing lesions induced by human papillomavirus (HPV) 16 and 18 that revealed integrated viral genome copies in the vast majority of cervical cancer cells. However, a substantial fraction of cervical cancers is associated with other HR-HPV types for which virtually no data concerning their integration status have been reported so far. Here, we compared integration frequencies of the five most common oncogenic HPV types (HPV16, 18, 31, 33, and 45) in a series of 835 cervical samples using a specific mRNA-based PCR assay (Amplification of Papillomavirus Oncogene Transcripts). Most precancerous lesions displayed exclusively episomal viral genomes, whereas 62% of the carcinomas had integrated viral genomes. However, the frequency of integrated HR-HPV genomes showed marked differences for individual HR-HPV types. HPV16, 18, and 45 were found substantially more often in the integrated state compared with HPV types 31 and 33. The analysis of the median age of patients with high-grade precancerous lesions and invasive cancers suggests that precancers induced by HPV types 18, 16, and 45 progress to invasive cervical cancer in substantially less time compared with precancers induced by HPV types 31 and 33. These findings suggest that integration of oncogenic HPV genomes in cervical lesions is a consequence rather than the cause of chromosomal instability induced by deregulated HR-HPV E6-E7 oncogene expression. Distinct HR-HPV types apparently provoke chromosomal instability in their host cells to a different extent than is reflected by their integration frequencies in advanced lesions and the time required for CIN 3 lesions to progress to invasive cancer.