1. Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription
- Author
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Pang, John, Nguyen, Nam, Luebeck, Jens, Ball, Laurel, Finegersh, Andrey, Ren, Shuling, Nakagawa, Takuya, Flagg, Mitchell, Sadat, Sayed, Mischel, Paul S, Xu, Guorong, Fisch, Kathleen, Guo, Theresa, Cahill, Gabrielle, Panuganti, Bharat, Bafna, Vineet, and Califano, Joseph
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Dental/Oral and Craniofacial Disease ,Digestive Diseases ,Genetics ,Infectious Diseases ,Women's Health ,Human Genome ,Cancer Genomics ,Sexually Transmitted Infections ,Cancer ,2.1 Biological and endogenous factors ,Alphapapillomavirus ,DNA ,Circular ,DNA ,Viral ,Head and Neck Neoplasms ,Humans ,Oncogene Proteins ,Viral ,Oncogenes ,Oropharyngeal Neoplasms ,Papillomaviridae ,Papillomavirus Infections ,Proteomics ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeHuman papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood.Experimental designForty-four primary tumor tissue samples were obtained from a cohort of patients with HPV-positive oropharynx squamous cell carcinoma (OPSCC). Twenty-eight additional HPV oropharyngeal cancer (HPVOPC) tumors from The Cancer Genome Atlas (TCGA) project were analyzed as a separate validation cohort. Genomic, transcriptomic, proteomic, computational, and functional analyses of HPVOPC were applied to these datasets.ResultsOur analysis revealed circular, oncogenic DNA in nearly all HPVOPC, with circular human and human-viral hybrid ecDNA present in over a third of HPVOPC and viral circular DNA in remaining tumors. Hybrid ecDNA highly express fusion transcripts from HPV promoters and HPV oncogenes linked to downstream human transcripts that drive oncogenic transformation and immune evasion, and splice multiple, diverse human acceptors to a canonical SA880 viral donor site. HPVOPC have high E6*I expression with specific viral oncogene expression pattern related to viral or hybrid ecDNA composition.ConclusionsNonchromosomal circular oncogenic DNA is a dominant feature of HPVOPC, revealing an unanticipated link between HPV and ecDNA that leverages the power of extrachromosomal inheritance to drive HPV and somatic oncogene expression.
- Published
- 2021