Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism
Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism
复制标题
宫颈癌中 HPV 整合的全基因组分析确定了基因组热点簇和潜在的微同源介导的整合机制
DOI：
10.1038/ng.3178
复制
发表时间：
2015-02-01
期刊：
影响因子：
30.8
通讯作者：
Ma, Ding
中科院分区：
文献类型：
--
作者：
Hu, Zheng;Zhu, Da;Ma, Ding
人乳头瘤病毒（HPV）整合是宫颈癌发生过程中的一个关键遗传事件（1）。通过进行全基因组测序和高通量病毒整合检测，我们在26例宫颈上皮内瘤变、104例宫颈癌和5个细胞系中确定了3667个HPV整合断点。除了重新计算先前报道的频繁整合位点POU5F1B（9.7%）、FHIT（8.7%）、KLF12（7.8%）、KLF5（6.8%）、LRP1B（5.8%）和LEPREL1（4.9%）的频率外，我们还发现了新的热点HMGA2（7.8%）、DLG2（4.9%）和SEMA3D（4.9%）。当HPV整合到FHIT和LRP1B的内含子中时，这两种蛋白的表达下调。当HPV整合到侧翼区域时，MYC和HMGA2的蛋白表达升高。此外，在整合断点附近，人类基因组和HPV基因组之间的微同源序列显著富集，这表明病毒和人类DNA之间的融合可能是通过微同源介导的DNA修复途径发生的（2）。我们的数据为HPV整合驱动的宫颈癌发生提供了见解。
Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis. By conducting whole-genome sequencing and high-throughput viral integration detection, we identified 3,667 HPV integration breakpoints in 26 cervical intraepithelial neoplasias, 104 cervical carcinomas and five cell lines. Beyond recalculating frequencies for the previously reported frequent integration sitesPOU5F1B(9.7%),FHIT(8.7%),KLF12(7.8%),KLF5(6.8%),LRP1B(5.8%) andLEPREL1(4.9%), we discovered new hot spotsHMGA2(7.8%),DLG2(4.9%) andSEMA3D(4.9%). Protein expression fromFHITandLRP1Bwas downregulated when HPV integrated in their introns. Protein expression fromMYCandHMGA2was elevated when HPV integrated into flanking regions. Moreover, microhomologous sequence between the human and HPV genomes was significantly enriched near integration breakpoints, indicating that fusion between viral and human DNA may have occurred by microhomology-mediated DNA repair pathways. Our data provide insights into HPV integration-driven cervical carcinogenesis.