Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer. To resolve genome dysregulation associated with HPV integration, we performed Oxford Nanopore long-read sequencing on 72 cervical cancer genomes from an Ugandan dataset that was previously characterized using short-read sequencing. We found recurrent structural rearrangement patterns at HPV integration events, which we categorized as: del(etion)-like, dup(lication)-like, translocation, multibreakpoint, or repeat region integrations. Integrations involving amplified HPV-human concatemers, particularly multibreakpoint events, frequently harbored heterogeneous forms and copy numbers of the viral genome. Transcriptionally active integrants were characterized by unmethylated regions in both the viral and human genomes downstream from the viral transcription start site, resulting in HPV-human fusion transcripts. In contrast, integrants without evidence of expression lacked consistent methylation patterns. Furthermore, whereas transcriptional dysregulation was limited to genes within 200 kilobases of an HPV integrant, dysregulation of the human epigenome in the form of allelic differentially methylated regions affected megabase expanses of the genome, irrespective of the integrant's transcriptional status. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

中文翻译：

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人瘤病毒整合事件中病毒和人类基因组的重排及其等位基因对癌症基因组调控的特异性影响


人瘤病毒 （HPV） 整合与将 HPV 感染转化为癌症有关。为了解决与 HPV 整合相关的基因组失调，我们对来自乌干达数据集的 72 个宫颈癌基因组进行了 Oxford Nanopore 长读长测序，该数据集之前使用短读长测序进行表征。我们在 HPV 整合事件中发现了复发的结构重排模式，我们将其分为： del（etion） 样、dup（lication） 样、易位、多断点或重复区域整合。涉及扩增的 HPV-人连接异构体的整合，特别是多断点事件，通常包含病毒基因组的异质形式和拷贝数。转录活性整合子的特征是病毒转录起始位点下游病毒和人类基因组中的未甲基化区域，导致 HPV-人类融合转录本。相比之下，没有表达证据的整合子缺乏一致的甲基化模式。此外，虽然转录失调仅限于 HPV 整合子 200 kb 以内的基因，但等位基因差异甲基化区域形式的人类表观基因组失调影响了基因组的兆碱基扩展，无论整合子的转录状态如何。通过阐明 HPV 整合的结构、表观遗传学和等位基因特异性影响，我们深入了解整合 HPV 在宫颈癌中的作用。