Defining HPV integration sites of unknown significance in invasive cervical cancer

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PROJECT SUMMARY/ABSTRACT Integration of the human papillomavirus (HPV) into the host genome is a dominant feature of invasive cervical cancer (ICC). Genomic coordinates of integration sites have been identified in many tumors, but little is known about the nature of the cis genomic changes at these sites or how they might promote ICC. Harnessing data from The Cancer Genome Atlas (TCGA) along with patient-matched long-read sequencing of HPV integration sites will define novel genes/pathways affecting ICC outcome. Aim 1 will define HPV integration sites in the TCGA- MCW cervical cancer cohort using newly developed HPV DNA capture for long-read sequencing. Once identified, we will annotate each integration site using TCGA data sources that document complex rearrangements, copy number variation, clonality, loss-of-heterozygosity, epigenetic signature, gene expression, and chimerism. Characteristics of integration sites found by this in- depth annotation will enable us to prioritize putative integration driver genes to be further studied in Aim 2, when we will establish the biological relevance of a few genes influenced by our high- priority HPV integration sites. Using a panel of available cervical cancer cell lines, we will then characterize the functional consequences of manipulating those genes whose functions in cervical cancer have yet to be determined. The proposed study is expected to identify downstream molecular drivers of specific HPV integration sites, thus revealing novel ICC-specific therapeutic vulnerabilities that may be targeted for treatment.