Genomic organization of amplified MYC genes suggests distinct mechanisms of amplification in tumorigenesis
Genomic organization of amplified MYC genes suggests distinct mechanisms of amplification in tumorigenesis
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DOI：
10.1158/0008-5472.can-04-2802
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Bensimon, A
中科院分区：
文献类型：
--
作者：
Herrick, J;Conti, C;Bensimon, A
人乳头瘤病毒 (HPV) 基因组整合到宿主基因组中与 HPV E2 基因的破坏以及病毒和侧翼细胞序列的扩增和重排有关。共扩增 HPV 序列和癌基因的基因组结构的分子特征提供了有关扩增机制及其在致癌作用中的作用的重要信息。通过对两种宫颈癌衍生细胞系中的拉伸 DNA 分子进行荧光杂交，我们阐明了包含超过数百个碱基的 HPV/myc 基因的扩增区域的基因组结构。单个 DNA 分子上杂交信号的直接可视化表明，过度复制和断裂融合桥型机制与 HPV 宫颈癌相关的基因组不稳定性有关。对另外两种生殖器癌症来源的细胞系的进一步分析揭示了一个反复出现的扩增基序，可能是由涉及病毒整合时过度复制的常见机制产生的。有趣的是，不同的扩增模式似乎与疾病结果相关，从而为 HPV 相关的癌症发生和肿瘤进展提供了新的见解。
Integration of the human papillomavirus (HPV) genome into the host genome is associated with the disruption of the HPV E2 gene and with amplification and rearrangement of the viral and flanking cellular sequences. Molecular characterization of the genomic structures of coamplified HPV sequences and oncogenes provides essential information concerning the mechanisms of amplification and their roles in carcinogenesis. Using fluorescent hybridization on stretched DNA molecules in two cervical cancer-derived cell lines, we have elucidated the genomic structures of amplified regions containing HPV/myc genes over several hundreds of kilobases. Direct visualization of hybridization signals on individual DNA molecules suggests that overreplication and breakage-fusion-bridge-type mechanisms are involved in the genomic instability associated with HPV cervical cancers. Further analysis from two other genital cancer-derived cell lines reveals a recurrent motif of amplification, probably generated by a common mechanism involving overreplication upon viral integration. Interestingly, different amplification patterns seem to be correlated with the disease outcome, thus providing new insights into HPV-related cancer development and tumor progression.