Kay Jayachandrana, Rashmi Pillaib, Matthew Inkmana, Fiona Ruiza, Jace Webstera, Julie Schwarza, Christopher Mahera, Jin Zhanga
aWashington University School of Medicine, St. Louis, MO, United States; bAgilent Technologies, San Diego, CA, United States
BACKGROUND: Cervical cancer is a common gynecological tumor, primarily caused by HPV infection. Integration of HPV into the human genome allows aberrant expression of HPV oncogenes E6 and E7. However, whether HPV-human gene fusions arise from these events and their effects on human gene partners are less studied.
METHODS: Using TCGA cervical cancer RNA-seq data (N=304) and 3 cell lines, we modified and applied our human gene fusion discovery tool, INTEGRATE, to detect chimeric virus-host transcripts, followed by manual inspection for expressed HPV-human gene fusions using NCBI’s BLAST. HPV-human fusion junctions were validated using qRT-PCR, and their effects on human gene partners were characterized.
RESULTS: Greater than 30% of samples contain at least 1 HPV-human transcript with a clear exon-to-exon structure. 22% of these HPV-human fusions share the same human gene partner with at least 1 human-human gene fusion in other samples. qRT-PCR validated HPV-human fusions in the cell lines, including a chimeric transcript with lincRNA LINC00393, also found in 2 TCGA samples. Notably, HPV fused recurrently to the PVT1 and CASC8 lincRNAs in the 8q24 region, which upregulated MYC gene expression. For samples involving multiple detected HPV-human breakpoints in the same gene, we propose the transcribed RNA exhibits a looping structure previously observed in DNA.
CONCLUSION: We showed that HPV-human gene fusion transcripts can be detected using RNA-seq data, which affect human cancer gene expression.