Common fragile sites are preferential targets for HPV16 integrations in cervical tumors
Common fragile sites are preferential targets for HPV16 integrations in cervical tumors
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DOI：
10.1038/sj.onc.1206170
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发表时间：
2003-02-27
期刊：
影响因子：
8
通讯作者：
Smith, DI
中科院分区：
文献类型：
--
作者：
Thorland, EC;Myers, SL;Smith, DI
宫颈癌的发生与人乳头瘤病毒(HPV)感染密切相关。HPV整合到感染的宫颈细胞基因组中与恶性表型的获得暂时相关。从细胞遗传学和分子水平观察到宫颈癌中HPV整合部位与常见脆性部位(CFSS)的位置之间的关系。为了在分子水平上进一步探索这种关系，我们使用RS-PCR快速分离了26例原发性宫颈肿瘤中HPV16整合位点两侧的细胞序列。根据这些侧翼序列分离了人的细菌人工染色体克隆，并将其作为荧光原位杂交的探针，应用于蜂毒灵刺激的中期分裂相上。我们的数据表明，宫颈肿瘤中有11/23的HPV16整合发生在CFSS中(P<；0.001)。此外，我们还发现在整合所针对的细胞序列中经常发生缺失和复杂的重排，整合集中在FRA13C(13q22)、FRA3B(3p14.2)和FRA17B(17q23)中。最后，我们的数据表明，细胞基因，如Notch 1，被HPV16整合破坏，这可能与恶性表型有关。
The development of cervical cancer is highly associated with human papillomavirus (HPV) infection. HPV integration into the genome of infected cervical cells is temporally associated with the acquisition of the malignant phenotype. A relationship between the sites of HPV integration in cervical cancer and the position of the common fragile sites (CFSs) has been observed at both the cytogenetic and molecular levels. To further explore this relationship at the molecular level, we used RS-PCR to rapidly isolate cellular sequences flanking the sites of HPV16 integration in 26 primary cervical tumors. Human bacterial artificial chromosome clones were isolated based on these flanking sequences and used as probes for fluorescence in situ hybridization on aphidicolin-stimulated metaphases. Our data demonstrate that 11/23 HPV16 integrations in cervical tumors occurred within CFSs (P < 0.001). In addition, we show that deletions and complex rearrangements frequently occur in the cellular sequences targeted by the integrations and that integrations cluster in FRA13C (13q22), FRA3B (3p14.2), and FRA17B (17q23). Finally, our data suggest that cellular genes, such as Notch 1, are disrupted by the HPV16 integrations, which may contribute to the malignant phenotype.