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Nat Genet. 2015 Feb;47(2):158-63. doi: 10.1038/ng.3178. Epub 2015 Jan 12.

Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism.

Author information

1
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
2
Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
3
1] Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. [2] School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, China.
4
1] Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China. [2] Department of Computer Science, City University of Hong Kong, Hong Kong, China.
5
Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China.
6
Department of Computer Science, City University of Hong Kong, Hong Kong, China.
7
WuHan Frasergen Bioinformatics Co., Ltd , Wuhan, China.
8
Wuhan Institute of Biotechnology, Wuhan, China.
9
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
10
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.

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.

PMID:
25581428
DOI:
10.1038/ng.3178
[Indexed for MEDLINE]

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