Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer

Liyuan Zhou; Qiongzi Qiu; Qing Zhou; Jianwei Li; Mengqian Yu; Kezhen Li; Lingling Xu; Xiaohui Ke; Haiming Xu; Bingjian Lu; Hui Wang; Weiguo Lu; Pengyuan Liu; Yan Lu

doi:10.1038/s41467-022-30190-1

Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer

Nat Commun. 2022 May 10;13(1):2563. doi: 10.1038/s41467-022-30190-1.

Authors

Liyuan Zhou^#¹, Qiongzi Qiu^#², Qing Zhou^#², Jianwei Li², Mengqian Yu¹, Kezhen Li³, Lingling Xu¹, Xiaohui Ke⁴, Haiming Xu⁵, Bingjian Lu^{2

6}, Hui Wang^{2

6}, Weiguo Lu^{7

8}, Pengyuan Liu^{9

10

11

12}, Yan Lu^{13

14

15}

Affiliations

¹ Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Obstetrics and Gynecology, Wenzhou Central Hospital, Wenzhou, Zhejiang, 325000, China.
⁵ Institute of Bioinformatics, Zhejiang University, Hangzhou, China.
⁶ Cancer center, Zhejiang University, Hangzhou, China.
⁷ Cancer center, Zhejiang University, Hangzhou, China. lbwg@zju.edu.cn.
⁸ Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. lbwg@zju.edu.cn.
⁹ Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. pyliu@zju.edu.cn.
¹⁰ Cancer center, Zhejiang University, Hangzhou, China. pyliu@zju.edu.cn.
¹¹ Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. pyliu@zju.edu.cn.
¹² Department of Physiology and Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. pyliu@zju.edu.cn.
¹³ Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. yanlu76@zju.edu.cn.
¹⁴ Cancer center, Zhejiang University, Hangzhou, China. yanlu76@zju.edu.cn.
¹⁵ Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. yanlu76@zju.edu.cn.

^# Contributed equally.

Abstract

Integration of human papillomavirus (HPV) DNA into the human genome is considered as a key event in cervical carcinogenesis. Here, we perform comprehensive characterization of large-range virus-human integration events in 16 HPV16-positive cervical tumors using the Nanopore long-read sequencing technology. Four distinct integration types characterized by the integrated HPV DNA segments are identified with Type B being particularly notable as lacking E6/E7 genes. We further demonstrate that multiple clonal integration events are involved in the use of shared breakpoints, the induction of inter-chromosomal translocations and the formation of extrachromosomal circular virus-human hybrid structures. Combined with the corresponding RNA-seq data, we highlight LINC00290, LINC02500 and LENG9 as potential driver genes in cervical cancer. Finally, we reveal the spatial relationship of HPV integration and its various structural variations as well as their functional consequences in cervical cancer. These findings provide insight into HPV integration and its oncogenic progression in cervical cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinogenesis
Cervix Uteri / pathology
DNA, Viral / genetics
Female
Humans
Oncogene Proteins, Viral* / genetics
Papillomavirus Infections* / complications
Papillomavirus Infections* / genetics
Uterine Cervical Neoplasms* / pathology
Virus Integration / genetics

Substances

DNA, Viral
Oncogene Proteins, Viral