title: HPV16 integration probably contributes to cervical oncogenesis through interrupting tumor suppressor genes and inducing chromosome instability.
abstract: The integration of human papilloma virus (HPV) into host genome is one of the critical steps that lead to the progression of precancerous lesion into cancer. However, the mechanisms and consequences of such integration events are poorly understood. This study aims to explore those questions by studying high risk HPV16 integration in women with cervical intraepithelial neoplasia (CIN) and cervical squamous cell carcinoma (SCC).
  
  
  
  Specifically, HPV integration status of 13 HPV16-infected patients were investigated by ligation-mediated PCR (DIPS-PCR) followed by DNA sequencing.
  
  
  
  In total, 8 HPV16 integration sites were identified inside or around genes associated with cancer development. In particular, the well-studied tumor suppressor genes SCAI was found to be integrated by HPV16, which would likely disrupt its expression and therefore facilitate the migration of tumor. On top of that, we observed several cases of chromosome translocation events coincide with HPV integration, which suggests the existence of chromosome instability. Additionally, short overlapping sequences were observed between viral derived and host derived fragments in viral-cellular junctions, indicating that integration was mediated by micro homology-mediated DNA repair pathway.
  
  
  
  Overall, our study suggests a model in which HPV16 might contribute to oncogenesis not only by disrupting tumor suppressor genes, but also by inducing chromosome instability.
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
authors.forename: Jun-Wei
authors.initials: JW
authors.lastname: Zhao
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Abbey College Cambridge, Homerton Gardens, Cambridge, CB2 8EB, UK.
authors.forename: Tai-Lin
authors.initials: TL
authors.lastname: Zhu
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Yu
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
authors.forename: Fan-Fei
authors.initials: FF
authors.lastname: Kong
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China.
authors.forename: Ling-Fei
authors.initials: LF
authors.lastname: Han
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge, CB2 3EH, UK. dschen2016@gmail.com.|Fitzwilliam College, University of Cambridge, Storey's Way, Cambridge, CB3 0DG, UK. dschen2016@gmail.com.
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Chen
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China. fang_li@tongji.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
mesh_terms: D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000821:virology*; D043171:Chromosomal Instability; D004279:DNA, Viral / Q000235:genetics*; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D025941:Protein Interaction Mapping; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000821:virology*; D016662:Virus Integration; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000821:virology*
chemical_list: D004279:DNA, Viral; C540922:SCAI protein, human; D014157:Transcription Factors
keywords: Cervical oncogenesis; Chromosome instability; HPV16; Integration