Grant: Project Grant

Human papillomavirus (HPV) causes >99% of cervical cancers and has a particularly deadly impact on sub-Saharan African females. Some strains of HPV can integrate their DNA into the DNA of cervical cells, which results in increased production of cancer causing viral proteins and is often the first step towards developing cervical cancer. This integration involves breaking the cervical cell's DNA. From work in other cancers, we know that breaking a cell's DNA (e.g. with chemicals or radiation) can result in dramatic rearrangements of large segments of cancer cell DNA. We now want to know whether DNA breakage caused by HPV results in dramatic rearrangements in cervical cancer. Such rearrangements of human genomes have been difficult to study due to the limitations of conventional genomics approaches. Fortuitously, a newer genomics approach, known as long-read sequencing, can sequence DNA fragments 100 times longer than the older approach, offering an opportunity to study, for the first time, unexplored damage that HPV might cause to the human genome and the role of that damage in causing cancer. We used long-read sequencing to collect preliminary data from two cervical cancer samples from Uganda to reveal previously unknown DNA rearrangements that were not found in analyses of short-read sequencing of the same samples. For example, we found some HPV-associated human genome rearrangements resulted in human cancer genes from different chromosomes being fused together, pointing to the possibility that we might discover new oncogenic mechanisms. We aim to explore such potentially important rearrangements using long-read sequencing of 50 cervical cancers chosen from our samples from Uganda. Long-read sequencing of these tumours will reveal previously hidden information on how HPV integration causes wide-spread DNA damage and may lead to identification of new therapeutic targets in a population that is historically underrepresented in cancer genomics research.