Interview: Resolving complex genomic structures and regulation patterns in cervical cancer

Vanessa Porter is a PhD candidate in Dr. Marco Marra’s lab at the Canada’s Michael Smith Genome Sciences Centre in Vancouver, where she uses nanopore sequencing to investigate how human papillomavirus (HPV) in different contexts affects the structure and regulation of cervical cancer genomes using multi-omics analyses. We caught up with Vanessa to discuss her current research interests, what led her to focus on cancer research, and how nanopore sequencing is helping our understanding of HPV integration in the human genome. You can hear more about Vanessa Porter’s work in her webinar ‘Resolving complex genomic structures and regulation patterns in cervical cancer’.

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What are your current research interests?

My research interests lie in the integration of Oxford Nanopore long-read technology with other multi-omic sequencing data to analyse the genomic and epigenomic features of tumours infected with human papillomavirus (HPV). Previous research by our group has demonstrated that HPV significantly influences the epigenome of the tumours, particularly in the regions where the virus integrates its DNA into the human genome. I am especially fascinated by how complex genomic alterations in cancer genomes can impact genome regulation, both locally and across significant genomic distances. The presence of integrated HPV in tumour genomes offers a unique opportunity to explore how modifications to the DNA structure can affect epigenomic regulation in the surrounding area and beyond.

What first ignited your interest in genomics and what led you to focus on cancer research?

My research focus actually first began in cancer and then later turned to genomics to gain a big-picture understanding of gene dysregulation in tumours. In my Master’s degree, I used molecular biology techniques to study the function of proteins that were upregulated in a certain type of leukaemia. I was fascinated by the immense genetic changes that tumours undergo during tumourigenesis — the ways in which cells completely transform their genomes and regulatory patterns are so vast. I wanted to learn how to study these patterns at the genome-wide and multi-omic view, so during my PhD I transitioned into bioinformatics analyses of genomic data.

How is nanopore sequencing changing our understanding of the impact of HPV on the human genome?  How has it benefitted your work?

Nanopore sequencing has revolutionised our approach to studying viral integration, as mapping different copies of HPV to their integrated positions in the human genome has been a significant challenge within the field. This problem is compounded when there are multiple regions within the human genome that harbour integrated HPV. The distributed HPV segments share an identical sequence, making it impossible for conventional short-read genomics to differentiate between them. Long-read sequencing has enabled us to generate reads that span the entire integrated viral segment, eliminating any ambiguity regarding its genomic location. Furthermore, the added benefit of methylation detection has allowed us to layer epigenomic information on top of the genomic structure with ease.

What impact could the ability to classify HPV integration events have for cancer research?

Virus-driven cancers make up at least 10% of all cancers, and a significant portion of these tumours present with an integrated copy of the virus. Cancers driven by HPV are also still quite prevalent in unvaccinated men and in women from low- and middle-income countries that lack vaccine access. In addition, HPV integration is one of many complicated structure alterations that are seen in cancer. I believe that this study could have implications for understanding HPV biology, deciphering viral integration mechanisms, and also displaying methods in which we can relate cancer genome structure alterations to epigenomic dysregulation.

What have been the main challenges in your work and how have you approached them?

My work has presented several challenges, many of which are a direct result of the project's novelty. Since I am exploring a highly specific topic, there are limited published tools available to facilitate my analyses —  as a result, I had to develop and validate custom tools and methods to address my research questions effectively. Additionally, given the expansive scope of my research, I recognised the need for a collaborative team approach. To that end, I have sought out other graduate students, post-docs, and scientists with specialised expertise that complement my own, allowing us to work synergistically on this research question.

What’s next for your research?

We are planning to explore the transcriptome within HPV-infected cancers by using Oxford Nanopore’s long-read cDNA sequencing approach. We are interested in studying tumours that exhibit intriguing fusions between HPV and human genes, as well as fusions between multiple human genes. By examining the transcription of these fusions, we hope to gain a better understanding of their expression patterns and potential roles in HPV-driven cancers.