Oncogenic virus infections contribute to approximately 15% of the total cancer burden, causing 1.6 million new malignancies annually. HPV, HBV, and EBV are the three most hazardous oncogenic DNA viruses. One common feature is the insertion of their DNA into the human genome to further promote tumorigenesis. However, the insertional patterns and mechanisms are still poorly understood.
To systematically interrogate the integration profiles of HPV, HBV and EBV, we conducted genome-wide virus capture sequencing on 6075 possible HPV-related samples and two EBV-positive cell lines. We then applied detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR) on 397 cervical cancer samples, and collected the datasets of 1483 HPV-related cancers, 1070 HBV-related carcinomas, and 556 EBV-related tumors from public database. Furthermore, we developed and performed a novel pipeline named Viral Integration Pathway Analysis (VIPA) for diverse viruses in our own data and the collected public data.
We uncovered that the integration patterns of different HPV, HBV, and EBV genotypes were significantly distinct and non-randomly affected several key cancer-associated genes. This subtype-specific integration pattern for each virus supports the notion that different viral genotypes require differential treatment and should be treated as different viruses. Notably, 449 integration hotspots were shared by all three viruses, indicating the presence of pan-oncovirus integration hotspots. We further examined these integration hotspots and found that HPV, HBV, and EBV insertion events are predominately mediated by synthesis-dependent end joining, which is in contrast to the traditional view of classical non-homologous end-joining.
In summary, we report a genome-wide unbiased analysis of HPV, HBV and EBV insertional mutagenesis in our own data and the public data. We discovered HPV, HBV, and EBV share the same dominant SD-EJ integration mechanism during carcinogenesis. Our data provide a framework for patient stratification based on viral integration patterns and shed new light on novel therapeutic approaches to virus-induced cancers.
The First Affiliated Hospital, Sun Yat-sen University.
National Science and Technology Major Project of the Ministry of Science and Technology of China (No.2018ZX10301402).
All authors have declared no conflicts of interest.