Vinokurova Svetlana, Wentzensen Nicolas, Kraus Irene, Klaes Ruediger, Driesch Corina, Melsheimer Peter, Kisseljov Fjodor, Dürst Mattias, Schneider Achim, von Knebel Doeberitz Magnus
Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
Cancer Res. 2008 Jan 1;68(1):307-13. doi: 10.1158/0008-5472.CAN-07-2754.
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.
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，与癌前病变发展为浸润性癌相关。这一假说基于实验数据，表明HR-HPV E2基因功能的整合依赖性破坏对于实现肿瘤转化很重要，也基于通过分析人乳头瘤病毒（HPV）16和18诱导的病变所收集的临床数据，这些数据显示在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，目前几乎没有关于它们整合状态的数据报道。在此，我们使用基于特定mRNA的PCR检测方法（乳头瘤病毒癌基因转录本扩增），比较了835份宫颈样本中五种最常见致癌性HPV类型（HPV16、18、31、33和45）的整合频率。大多数癌前病变仅显示游离的病毒基因组，而62%的癌具有整合的病毒基因组。然而，整合的HR-HPV基因组频率在各HR-HPV类型之间存在显著差异。与HPV 31和33型相比，HPV16、18和45型以整合状态出现的频率要高得多。对高级别癌前病变和浸润性癌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所需的时间要短得多。这些发现表明，宫颈病变中致癌性HPV基因组的整合是HR-HPV E6-E7癌基因表达失调所诱导的染色体不稳定的结果而非原因。不同的HR-HPV类型显然在其宿主细胞中引发染色体不稳定的程度不同，这一点在晚期病变中的整合频率以及CIN 3病变进展为浸润性癌所需的时间上并未得到体现。
