Characterization of viral-cellular fusion transcripts in a large series of HPV16 and 18 positive anogenital lesions
Characterization of viral-cellular fusion transcripts in a large series of HPV16 and 18 positive anogenital lesions
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DOI：
10.1038/sj.onc.1205104
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发表时间：
2002-01-17
期刊：
影响因子：
8
通讯作者：
Doeberitz, MV
中科院分区：
文献类型：
--
作者：
Wentzensen, N;Ridder, R;Doeberitz, MV
持续的高危型人乳头瘤病毒（HR-HPV）感染诱发肛门生殖道的发育不良或癌症，最显著的是子宫颈。病毒基因组通常在早期发育不良中作为附加型分子持续存在和复制，而在晚期发育不良或宫颈癌中，HPV基因组经常整合到宿主细胞的染色体DNA中。以前的研究表明，通过整合HPV基因组修饰关键细胞序列可能显著促进肛门生殖器上皮的肿瘤转化（插入突变）。这促使我们在大量的生殖器病变中描述高危HPV基因组的整合位点。我们扩增了来自整合的HPV 16和HPV 18基因组的E6/E7癌基因转录物，并详细描述了共转录的细胞序列！64个原发性生殖器病变和5个宫颈癌细胞系。对这些融合转录物的细胞部分的数据库分析揭示了51个不同的整合位点，包括26个转录基因（14个已知基因，12个基因功能未知的EST序列）。17个序列与重复元件具有相似性，26个序列除基因组序列外未显示任何数据库匹配。染色体整合位点分布在几乎所有的人类染色体上。虽然我们发现HPV序列整合到癌症相关基因中，并靠近脆性位点，但没有发现优先位点或整合基序。这些数据表明，靶向插入突变可能发生在少数HPV诱导的肛门生殖器病变，但它是例外而不是规则。
Persistent high risk type human papillomavirus (HR - HPVs) infections induce dysplasia or cancer of the anogenital tract, most notably of the uterine cervix. The viral genome usually persists and replicates as an episomal molecule in early dysplasia, whereas in advanced dysplasia or cervical cancer HPV genomes are frequently integrated into the chromosomal DNA of the host cell. Previous studies suggested that modification of critical cellular sequences by integration of HPV genomes might significantly contribute to the neoplastic transformation of anogenital epithelia (insertional mutagenesis). This prompted us to characterize the integration loci of high risk HPV genomes in a large set of genital lesions. We amplified E6/E7 oncogene transcripts derived from integrated HPV16 and HPV18 genomes and characterized in detail the co-transcribed cellular sequences! of 64 primary genital lesions and five cervical cancer cell lines. Database analyses of the cellular parts of these fusion transcripts revealed 51 different integration loci, including 26 transcribed genes (14 known genes, 12 EST sequences with unknown gene function). Seventeen sequences showed similarity to repetitive elements, and 26 sequences did not show any database match other than genomic sequence. Chromosomal integration loci were distributed over almost all human chromosomes. Although we found HPV sequences integrated into cancer related genes and close to fragile sites, no preferential site or integration motif could be identified. These data demonstrate that target directed insertional mutagenesis might occur in few HPV-induced anogenital lesions, however, it is rather the exception than the rule.