BackgroundPersistent infection with human papillomaviruses (HPVs) has been associated with cervical intraepithelial neoplasia (CIN) and cervical cancer. However, why only a fraction of HPV cases progress to cancer is still unclear.MethodsWe focused on the heterogeneity, classification, evolution and dispersal of variants for 14 common HPV types in 262 HPV-positive patients with cervical lesions. The E6 and E7 genes of HPV were sequenced and compared with the HPV reference for sequence analysis. Phylogenetic trees were constructed using the neighbour-joining tree method with MEGA 7.0.ResultsIn this study, 233 E6 and 212 E7 sequences were successfully amplified by PCR, and these sequences were divided into 5 species groups: alpha-9 (HPV16, 31, 33, 52, 58), alpha-5 (HPV51), alpha-6 (HPV53, 66), alpha-7 (HPV18, 39, 59, 68) and alpha-10 (HPV6, 44). The incidence of high-grade squamous intraepithelial lesion (HSIL) in patients infected with alpha-9 HPV was significantly increased compared with other groups (P < 0.0001), especially HPV16 (P < 0.0001). Strikingly, E7 had significantly fewer nonsynonymous variants in the HSIL compared to

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High-risk human papillomavirus (hrHPV) infection and integration were considered as essential onset factors for the development of cervical cancer. However, the mechanism on how hrHPV integration influences the host genome structure remains not fully understood. In this study, we performed in situ high-throughput chromosome conformation capture (Hi-C) sequencing, chromatin immunoprecipitation and sequencing (ChIP-seq), and RNA-sequencing (RNA-seq) in two cervical cells, 1) NHEK normal human epidermal keratinocyte; and 2) HPV16-integrated SiHa tumorigenic cervical cancer cells. Our results reveal that the HPV-LINC00393 integrated chromosome 13 exhibited significant genomic variation and differential gene expression, which was verified by calibrated CTCF and H3K27ac ChIP-Seq chromatin restructuring. Importantly, HPV16 integration led to differential responses in topologically associated domain (TAD) boundaries, with a decrease in the tumor suppressor KLF12 expression downstream of LINC00393. Overall, this study provides significant insight into the understanding of HPV16 integration induced 3D structural changes and their contributions on tumorigenesis, which supplements the theory basis for the cervical carcinogenic mechanism of HPV16 integration.

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