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

Zheng Hu; Da Zhu; Wei Wang; Weiyang Li; Wenlong Jia; Xi Zeng; Wencheng Ding; Lan Yu; Xiaoli Wang; Liming Wang; Hui Shen; Changlin Zhang; Hongjie Liu; Xiao Liu; Yi Zhao; Xiaodong Fang; Shuaicheng Li; Wei Chen; Tang Tang; Aisi Fu; Zou Wang; Gang Chen; Qinglei Gao; Shuang Li; Ling Xi; Changyu Wang; Shujie Liao; Xiangyi Ma; Peng Wu; Kezhen Li; Shixuan Wang; Jianfeng Zhou; Jun Wang; Xun Xu; Hui Wang; Ding Ma

doi:10.1038/ng.3178

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

Zheng Hu, Da Zhu, Wei Wang, Weiyang Li, Wenlong Jia, Xi Zeng, Wencheng Ding, Lan Yu, Xiaoli Wang, Liming Wang, Hui Shen, Changlin Zhang, Hongjie Liu, Xiao Liu, Yi Zhao, Xiaodong Fang, Shuaicheng Li, Wei Chen, Tang Tang, Aisi FuZou Wang, Gang Chen, Qinglei Gao, Shuang Li, Ling Xi, Changyu Wang, Shujie Liao, Xiangyi Ma, Peng Wu, Kezhen Li, Shixuan Wang, Jianfeng Zhou, Jun Wang, Xun Xu, Hui Wang, Ding Ma

Publikation: Bidrag til tidsskrift › Letter › peer review

391 Citationer (Scopus)

Abstract

Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis¹. 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 pathways². Our data provide insights into HPV integration-driven cervical carcinogenesis.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	47
Udgave nummer	2
Sider (fra-til)	158-63, 2 unpag. pages
Antal sider	8
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3178
Status	Udgivet - feb. 2015

Adgang til dokumentet

10.1038/ng.3178

Citationsformater

Hu, Z., Zhu, D., Wang, W., Li, W., Jia, W., Zeng, X., Ding, W., Yu, L., Wang, X., Wang, L., Shen, H., Zhang, C., Liu, H., Liu, X., Zhao, Y., Fang, X., Li, S., Chen, W., Tang, T., ... Ma, D. (2015). Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nature Genetics, 47(2), 158-63, 2 unpag. pages. https://doi.org/10.1038/ng.3178

Hu, Z, Zhu, D, Wang, W, Li, W, Jia, W, Zeng, X, Ding, W, Yu, L, Wang, X, Wang, L, Shen, H, Zhang, C, Liu, H, Liu, X, Zhao, Y, Fang, X, Li, S, Chen, W, Tang, T, Fu, A, Wang, Z, Chen, G, Gao, Q, Li, S, Xi, L, Wang, C, Liao, S, Ma, X, Wu, P, Li, K, Wang, S, Zhou, J, Wang, J, Xu, X, Wang, H & Ma, D 2015, 'Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism', Nature Genetics, bind 47, nr. 2, s. 158-63, 2 unpag. pages. https://doi.org/10.1038/ng.3178

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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 carcinogenesis1. 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 pathways2. Our data provide insights into HPV integration-driven cervical carcinogenesis.",

keywords = "Adult, Alphapapillomavirus, Base Sequence, Cell Line, Tumor, Cervical Intraepithelial Neoplasia, DNA, Viral, Down-Regulation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome, Human, Genome, Viral, Genome-Wide Association Study, Humans, Middle Aged, Molecular Sequence Data, Papillomavirus Infections, Sequence Analysis, DNA, Up-Regulation, Uterine Cervical Neoplasms, Virus Integration",

author = "Zheng Hu and Da Zhu and Wei Wang and Weiyang Li and Wenlong Jia and Xi Zeng and Wencheng Ding and Lan Yu and Xiaoli Wang and Liming Wang and Hui Shen and Changlin Zhang and Hongjie Liu and Xiao Liu and Yi Zhao and Xiaodong Fang and Shuaicheng Li and Wei Chen and Tang Tang and Aisi Fu and Zou Wang and Gang Chen and Qinglei Gao and Shuang Li and Ling Xi and Changyu Wang and Shujie Liao and Xiangyi Ma and Peng Wu and Kezhen Li and Shixuan Wang and Jianfeng Zhou and Jun Wang and Xun Xu and Hui Wang and Ding Ma",

year = "2015",

month = feb,

doi = "10.1038/ng.3178",

language = "English",

volume = "47",

pages = "158--63, 2 unpag. pages",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism

AU - Hu, Zheng

AU - Zhu, Da

AU - Wang, Wei

AU - Li, Weiyang

AU - Jia, Wenlong

AU - Zeng, Xi

AU - Ding, Wencheng

AU - Yu, Lan

AU - Wang, Xiaoli

AU - Wang, Liming

AU - Shen, Hui

AU - Zhang, Changlin

AU - Liu, Hongjie

AU - Liu, Xiao

AU - Zhao, Yi

AU - Fang, Xiaodong

AU - Li, Shuaicheng

AU - Chen, Wei

AU - Tang, Tang

AU - Fu, Aisi

AU - Wang, Zou

AU - Chen, Gang

AU - Gao, Qinglei

AU - Li, Shuang

AU - Xi, Ling

AU - Wang, Changyu

AU - Liao, Shujie

AU - Ma, Xiangyi

AU - Wu, Peng

AU - Li, Kezhen

AU - Wang, Shixuan

AU - Zhou, Jianfeng

AU - Wang, Jun

AU - Xu, Xun

AU - Wang, Hui

AU - Ma, Ding

PY - 2015/2

Y1 - 2015/2

N2 - Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis1. 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 pathways2. Our data provide insights into HPV integration-driven cervical carcinogenesis.

AB - Human papillomavirus (HPV) integration is a key genetic event in cervical carcinogenesis1. 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 pathways2. Our data provide insights into HPV integration-driven cervical carcinogenesis.

KW - Adult

KW - Alphapapillomavirus

KW - Base Sequence

KW - Cell Line, Tumor

KW - Cervical Intraepithelial Neoplasia

KW - DNA, Viral

KW - Down-Regulation

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Genome, Human

KW - Genome, Viral

KW - Genome-Wide Association Study

KW - Humans

KW - Middle Aged

KW - Molecular Sequence Data

KW - Papillomavirus Infections

KW - Sequence Analysis, DNA

KW - Up-Regulation

KW - Uterine Cervical Neoplasms

KW - Virus Integration

U2 - 10.1038/ng.3178

DO - 10.1038/ng.3178

M3 - Letter

C2 - 25581428

SN - 1061-4036

VL - 47

SP - 158-63, 2 unpag. pages

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -