Article Text


Original article
Comprehensive genomic variation profiling of cervical intraepithelial neoplasia and cervical cancer identifies potential targets for cervical cancer early warning
  1. Jian Huang1,2,
  2. Zhaoyang Qian3,4,
  3. Yuhua Gong5,
  4. Yanzhou Wang6,
  5. Yanfang Guan5,
  6. Yingxin Han1,
  7. Xin Yi5,
  8. Wanqiu Huang1,
  9. Liyan Ji5,
  10. Jiajia Xu3,4,
  11. Mengyuan Su3,4,
  12. Qing Yuan1,
  13. Shujian Cui2,
  14. Jinling Zhang7,
  15. Chaohui Bao1,
  16. Weilong Liu8,
  17. Xi Chen3,4,
  18. Ming Zhang3,4,
  19. Xiaohuan Gao3,4,
  20. Renhua Wu3,4,
  21. Yinxin Zhang1,
  22. Huicheng Xu6,
  23. Shida Zhu4,
  24. Hongmei Zhu3,4,
  25. Ling Yang5,
  26. Xun Xu4,
  27. Pingyu Zhou9,
  28. Zhiqing Liang6
  1. 1 Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
  2. 2 Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome at Shanghai, Shanghai, China
  3. 3 Binhai Genomics Institute, BGI-Tianjin, Tianjin, China
  4. 4 BGI-Shenzhen, Shenzhen, Guangdong, China
  5. 5 Geneplus-Beijing, Beijing, China
  6. 6 Department of Obstetrics and Gynecology, Southwestern Hospital, Third Military Medical University, Chongqing, China
  7. 7 Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, Shenzhen, China
  8. 8 Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People’s Hospital, Guangdong Medical University, Shenzhen, Guangdong, China
  9. 9 STD Institute, Shanghai Skin Disease Hospital, Tong Ji University, Shanghai, China
  1. Correspondence to Dr Jian Huang, Shanghai Jiao Tong University, Shanghai 200240, China; jianhuang{at}, Dr Pingyu Zhou, STD Institute, Shanghai Skin Disease Hospital, Tong Ji University, Shanghai 200050, China; zpyls{at} and Dr Zhiqing Liang, Department of Obstetrics & Gynecology, Southwestern Hospital, Third Military Medical University, Chongqing 400038, China; zhi.lzliang{at}


Background To better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC.

Methods We performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis.

Results Mutational analysis identified eight significantly mutated genes in CC including four genes (FAT1, MLL3, MLL2 and FADD), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs.

Conclusion Our results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC.

  • cervical cancer
  • pathogenesis
  • genomic variation
  • human papillomavirus integration

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  • JH, ZQ, YG and YW contributed equally.

  • Contributors JH, PZ and ZL conceived the project and JH and XY designed the experiments. YG, XX, YG, YH, SC, XG, YZ, SZ, JX, RW, HZ, LY and XY performed sequencing and ZQ, YG, LJ, XC, MZ, CB and JH analysed the sequencing data. WL and BZ performed the pathology experiments. QY performed the RNA interference experiments. MS performed the pathway analysis. JH, PZ and XY contributed reagents, materials and analysis tools. ZL, PZ, YW and HX contributed the samples. JH, ZQ and YG integrated, analysed and interpreted all data. JH contributed to the supervision of the work. JH, YHG and ZYQ wrote the manuscript with the assistance and final approval of all authors.

  • Funding This work was supported by grants from the National Natural Science Foundation of China (81872274), the China National Key Projects for Infectious Disease (2017ZX10203207), the project of Precision Medicine of Southwestern Hospital (SWH2016ZDCX1013), the Clinical Research Plan of Shanghai Hospital Development Center (16CR1029B and 16CR3111B), the Chinese National Key Program on Basic Research (2014CB965002) and the Shanghai Commission for Science and Technology (15431902900).

  • Competing interests None declared.

  • Ethics approval This study was approved by the Research Ethics Committee of Southwestern Hospital (No. 2014 – 016) and EthicsCommittee of the Shanghai Skin Disease Hospital (No. SKIN2015-010) .

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First. Dr Pingyu Zhou’s corresponding address has been corrected.

  • Patient consent for publication Not required.

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