title: Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism.
abstract: 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 sites POU5F1B (9.7%), FHIT (8.7%), KLF12 (7.8%), KLF5 (6.8%), LRP1B (5.8%) and LEPREL1 (4.9%), we discovered new hot spots HMGA2 (7.8%), DLG2 (4.9%) and SEMA3D (4.9%). Protein expression from FHIT and LRP1B was downregulated when HPV integrated in their introns. Protein expression from MYC and HMGA2 was 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.
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Da
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 1] Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. [2] School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China.
authors.forename: Weiyang
authors.initials: W
authors.lastname: Li
authors.affiliation: 1] Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. [2] Department of Computer Science, City University of Hong Kong, Hong Kong, China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Jia
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Liu
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Fang
authors.affiliation: Department of Computer Science, City University of Hong Kong, Hong Kong, China.
authors.forename: Shuaicheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: WuHan Frasergen Bioinformatics Co., Ltd , Wuhan, China.
authors.forename: Tang
authors.initials: T
authors.lastname: Tang
authors.affiliation: Wuhan Institute of Biotechnology, Wuhan, China.
authors.forename: Aisi
authors.initials: A
authors.lastname: Fu
authors.affiliation: Wuhan Institute of Biotechnology, Wuhan, China.
authors.forename: Zou
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xi
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Changyu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Shujie
authors.initials: S
authors.lastname: Liao
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Kezhen
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1] Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. [2] School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China. [3] Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia. [4] The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. [5] Centre for iSequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
mesh_terms: D000328:Adult; D052685:Alphapapillomavirus / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D016679:Genome, Viral / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D030361:Papillomavirus Infections / Q000235:genetics* / Q000821:virology; D017422:Sequence Analysis, DNA; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology; D016662:Virus Integration; D002578:Uterine Cervical Dysplasia / Q000235:genetics* / Q000821:virology
chemical_list: D004279:DNA, Viral