Biology subjects

Corbett, R. D.

Publications and source records attributed to Corbett, R. D..

3 recordsLinked to original sources

bioRxiv2026

Allele-specific chromatin modifications of HPV-associated extrachromosomal DNAs in cervical cancer

Cervical cancer, a human papillomavirus (HPV) driven malignancy, is the fourth deadliest cancer in females. Approximately 25% of primary cervical cancers contain circular structures called extrachromosomal DNAs (ecDNAs), which can be entirely composed of human DNA (human-only ecDNAs) or a combination of HPV and human DNA sequences (HPV-human hybrid ecDNAs). Human-only ecDNAs harbour cancer-driving oncogenes, but epigenetic differences between human-only and HPV-human hybrid ecDNAs are unexplored. Here we report that 30% of cervical cancers contained at least one ecDNA. HPV-human hybrid ecDNAs contained more active enhancers and promoters than human-only ecDNAs and invariably contained the HPV oncogenes E6 and E7. These ecDNAs also contained an allelic hypomethylation region associated with putative human promoters, as well as enrichments for motifs associated with recombination hotspots. By leveraging long-read WGS phasing data to separate ChIP-seq data into alleles, we revealed allele-specific peaks in enhancers and promoters on ecDNAs, of which HPV-human hybrid ecDNAs contained a higher density. Overall, we found HPV-human hybrid and human-only ecDNAs differed in their regulation, often at an allele-specific level. Our study more firmly establishes the importance of epigenome disruption in cervical cancer and how structural variation, particularly surrounding HPV integration sites, may shape the surrounding regulatory architecture.

genomics↗

bioRxiv2023

Genomic structures and regulation patterns at HPV integration sites in cervical cancer

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We 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 we 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 neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

genomics↗

bioRxiv2019

Loss of CIC promotes mitotic dysregulation and chromosome segregation defects

CIC encodes a transcriptional repressor and MAPK signalling effector that is inactivated by loss-of-function mutations in several cancer types, consistent with a role as a tumour suppressor. Here, we used bioinformatic, genomic, and proteomic approaches to investigate CICs interaction networks. We observed both previously identified and novel candidate interactions between CIC and SWI/SNF complex members, and also observed novel interactions between CIC and cell cycle regulators and RNA processing factors. We found that CIC loss is associated with an increased frequency of mitotic defects in human cell lines and an in vivo mouse model and with dysregulated expression of mitotic regulators. We also observed aberrant splicing in CIC-deficient cell lines predominantly at 3 and 5 untranslated regions of genes, including genes involved in MAPK signalling, DNA repair, and cell cycle regulation. Our study thus characterises the complexity of CICs functional network and describes the effect of its loss on cell cycle regulation, mitotic integrity, and transcriptional splicing, thereby expanding our understanding of CICs potential roles in cancers. In addition, our work exemplifies how multi-omic, network-based analyses can be used to uncover novel insights into the interconnected functions of pleiotropic genes/proteins across cellular contexts. Simple summaryCapicua (CIC) is a gene that is frequently mutated in several cancer types, including stomach cancers and certain subtypes of brain tumours and sarcomas. CIC, the protein encoded by the CIC gene, has been shown to play a multitude of roles in both normal and cancer cell functions; however, most studies exploring these roles focus on a single aspect of CIC function and may therefore overlook complex interconnected activities in which CIC is involved. In this study, we have used multiple complementary approaches to obtain a broader view of CICs complex functional networks. We observed novel interactions (genetic or physical) between CIC and genes/proteins involved in various aspects of cellular function, including regulation of cell division and processing of RNA molecules. Altogether, our work characterises the complexity of CICs functional network and expands our understanding of its potential roles in cancer.

cancer biology↗