DNA aneuploidy and integration of human papillomavirus type 16 E6/E7 oncogenes in Intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri
DNA aneuploidy and integration of human papillomavirus type 16 E6/E7 oncogenes in Intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix uteri
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DOI：
10.1158/1078-0432.ccr-03-0565
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发表时间：
2004-05-01
影响因子：
11.5
通讯作者：
Doeberitz, MV
中科院分区：
文献类型：
--
作者：
Melsheimer, P;Vinokurova, S;Doeberitz, MV
目的：高危型人乳头瘤病毒(HR-HPV)E6-E7癌基因的表达日益失控，已被认为是宫颈不典型增生及其衍生癌发病机制中的主要转化因子。这些基因在上皮干细胞中的表达首先导致染色体不稳定，并诱导染色体非整倍体。据推测，这随后有利于HR-HPV基因组整合到细胞染色体中。这反过来导致病毒细胞融合转录本的表达，并进一步增强E6-E7癌蛋白的表达。因此，染色体的不稳定性和非整倍化似乎先于并有利于HR-HPV基因组的整合。实验设计：为了证明这一序列概念，我们分析了一系列HPV-16阳性的宫颈发育不良病变和癌中DNA非整倍化和整合的事件序列。对85例HPV16阳性宫颈病变(20例CIN1/2、50例CIN3和15例CxCaDNA)进行DNA倍体分析，并用逆转录聚合酶链式反应(RT-PCR法)检测HPVE6/E7癌基因的整合情况。结果：非整倍体和病毒基因组整合均与异型增生增加有关(P<；0.001，X(2)检验趋势)。此外，DNA非整倍体与病毒整合增加有关(P<；0.01，Fisher‘s Exact test)。20个具有整合病毒基因组的病变中有19个(95%)具有非整倍体细胞系，而在32个具有非整倍体细胞系的病变中只有19个(59%)具有整合的病毒基因组。结论：这些数据支持在宫颈不典型增生的进展过程中非整倍化先于HR-HPV基因组整合的假设。因此，解除病毒癌基因的表达似乎首先导致染色体不稳定和非整倍化，随后是HR-HPV基因组在受影响的细胞克隆中的整合。
Purpose: Increasingly deregulated expression of the E6-E7 oncogenes of high-risk human papillomaviruses (HR-HPVs) has been identified as the major transforming factor in the pathogenesis of cervical dysplasia and derived cancers. The expression of these genes in epithelial stem cells first results in chromosomal instability and induces chromosomal aneuploidy. It is speculated that this subsequently favors integration of HR-HPV genomes into cellular chromosomes. This in turn leads to expression of viral cellular fusion transcripts and further enhanced expression of the E6-E7 oncoproteins. Chromosomal instability and aneuploidization thus seems to precede and favor integration of HR-HPV genomes.Experimental Design: To prove this sequential concept, we analyzed here the sequence of events of DNA aneuploidization and integration in a series of HPV-16-positive cervical dysplastic lesions and carcinomas. Eighty-five punch biopsies of HPV-16-positive cervical lesions (20 CIN1/2, 50 CIN3, and 15 CxCa) were analyzed for DNA ploidy by DNA flow cytometry and for integration of HPV E6/E7 oncogenes using the amplification of papillomavirus oncogene transcripts assay, a reverse transcription-PCR method to detect integrate-derived human papillomavirus oncogene transcripts.Results: DNA aneuploidy and viral genome integration were both associated with increasing dysplasia (P < 0.001, chi(2) test for trend). In addition, DNA aneuploidy was associated with increased viral integration (P < 0.01, Fisher's exact test). Nineteen of 20 (95%) lesions with integrated viral genomes had aneuploid cell lines; however, only 19 of 32 (59%) lesions with aneuploid cell lines had integrated viral genomes.Conclusions: These data support the hypothesis that aneuploidization precedes integration of HR-HPV genomes in the progression of cervical dysplasia. Accordingly, deregulated viral oncogene expression appears to result first in chromosomal instability and aneuploidization and is subsequently followed by integration of HR-HPV genomes in the affected cell clones.