Comprehensive Genomic Variation Profiling of Cervical Intraepithelial Neoplasia and Cervical Cancer Identifies Potential Targets for Cervical Cancer Early Warning

Abstract

To better understand the pathogenesis of cervical cancer (CC), we systematically analyzed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC. We performed whole-genome sequencing (WGS) or whole-exome sequencing (WES) of 102 tumor-normal pairs and human papillomavirus (HPV) probe capture sequencing (HPCS) of 45 CCs, 44 cervical intraepithelial neoplasia (CIN) samples, and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis. 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. Our results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC. Funding Statement: This work was supported by grants from the National High Technology Research and Development Program of China (2012AA02A205), the Chinese National Key Program on Basic Research (2014CB965002), the National Natural Science Foundation of China (81272306 and 81472639), and the Shanghai Commission for Science and Technology (15431902900 and 15JC1403000). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Chinese CC patients were recruited under the approval of the Research Ethics Committee of Southwestern Hospital (No. 2014-016) and this project and protocols were conducted according to the Declaration of Helsinki. Informed consents were provided.