HPV- CCDC106 Integration Alters Local Chromosome Architecture and Hijacks an Enhancer by Remodeling the 3D Genome Structure in Cervical Cancer

Background: Integration of human papillomavirus (HPV) DNA into human genome is the reputed key driver of cervical cancer. However, the effects of HPV integration on chromatin structural organization and gene expression are largely unknown in such cancer. Methods: We investigated a cohort of 61 samples for HPV integration analysis. And selected a fresh cancer tissue from the set of clinical samples whose tissue only contained unique integration loci at CCDC106 and contained no HPV episomal DNA. A combination of WGS, RNA-seq, ChIP-seq and Hi-C data analysis were applied to identify the mechanisms of HPV integration in cervical carcinogenesis. IHC staining was used to validate the expression change after HPV-CCDC106 integration. Results: Based on the cohort of 61 samples, we identified a hot integrated site in the CCDC106 gene on chromosome 19. Additional analysis showed that this chromosome was enriched with genome variation and differential expression densities in the same HPV-CCDC106 integrated carcinoma sample. More importantly, we identified that HPV divided one topologically associated domain (TAD) into two TADs and hijacked an enhancer from PEG3 to CCDC106, thus leading to a decrease in PEG3 expression and high CCDC106 expression. This expression dysregulation was further confirmed by 10 samples exhibiting the same HPV-CCDC106 integration from our cohort. Interpretation: We found that HPV-CCDC106 integration tended to alter the architecture of the local chromosome and hijacked an enhancer via 3D genome structure remodeling, thus providing insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis. Funding Statement: This work was supported by Natural Science Foundation of China (81630060 to P. W., 81830074 and 81772786 to H. W., 81572569 to G. C., 31771402 to G. L. and 81772775 to J. W.), National Science and Technology Major Project (2018ZX10301402-002 to Q. G.), and the research-oriented clinician funding program of Tongji Medical College, Huazhong University of Science and Technology for P.W. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All tumor specimens, ThinPrep cytologic test (TCT) samples, and normal cervical tissues were obtained from the Department of Gynecological Oncology at Tongji Hospital under ethics board approval (TJ-IRB20180611) and with documented informed consent from all patients.