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Porter, Vanessa Lynn

University of British Columbia

Human papillomavirus (HPV) is the necessary driver of cervical cancer, a disease that largely affects females from underdeveloped nations and is prevalent among HIV-positive individuals. Altered regulation of the viral genome and HPV-driven genomic instability of the host genome are both implicated in transforming HPV infection into cancer. The regulation of viral genes often changes when the HPV genome becomes integrated into the host genome, which is seen in about 70% of cervical tumours. In addition, different high-risk HPV types have distinct disease characteristics, which has been underappreciated when studying HPV-driven molecular changes. To study HPV-driven molecular differences in cervical cancers, I analysed 118 tumours from Ugandan patients, of whom 72 were HIV-positive, using whole genome, whole transcriptome, and targeted epigenome sequencing. I detected HPV clade-specific differences in DNA methylation, promoter- and enhancer-associated histone marks, gene expression, and patient survival. The observed changes in epigenetic landscapes and the activation of cell invasion pathways may contribute to the reduced survival among patients infected with clade A7 HPV types. To resolve the dysregulation associated with HPV integration, I analysed 63 cervical cancer genomes using long-read sequencing. I identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon I termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighbouring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the HPV clade-associated tumour landscapes and integration-associated structural, epigenetic, and allele-specific impacts, I provide insight into the key oncogenic mechanisms of HPV in cervical cancer.

Text; Dataset

2024-03-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/87515

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/