Understanding the impact of non-coding mutations in the cancer genome.

About the Project

Oesophageal adenocarcinoma (OAC) is a deadly disease with poor survival statistics, is one of the highest incidence cancer types and is growing in prevalence, particularly in the developing world. A major reason for this, is the lack of treatment options, due mainly to our lack of knowledge of molecular targets that arise from a detailed molecular understanding of the disease. Over the past decade, our own work has helped to bridge this gap by investigating the gene regulatory mechanisms that lead to and maintain the cancer state in OAC (eg see Rogerson et al., 2019; Ogden et al., 2022; Ahmed et al., 2023; Yang et al., 2024). However, numerous questions remain. For example, although we have discovered that the precursor metaplastic state, Barrett’s oesophagus, shares gene regulatory networks with early developmental populations (Baker et al., 2025), how this is reconfigured in OAC progression and then reutilised following therapeutic drug treatment is poorly understood.

In addition to the transacting transcription factors, another important contributor to gene regulatory networks in cancer cells is the cis-regulatory landscape that is recognised and sculpted by these proteins. This consists primarily of promoter and enhancer elements but also insulators, silencers and as yet uncharacterised regulatory elements. Nothing is known about how these cis-regulatory elements are changed in OAC through mutational driver events, and yet these changes may have profound consequences. In this project we will harness genome-wide sequencing data and chromatin accessibility data to map mutational events in OAC cancer patients. These findings will be integrated with current models of the transcription factor networks operating in OAC. Findings will be functionally verified using massive parallel reporter assays (MPRAs) and key mutational events validated in OAC cells through CRISPR-mediated engineering of endogenous loci.

Outcome: We aim to develop a comprehensive understanding of how mutational events in OAC can directly affect the gene regulatory networks in OAC to drive cancer progression and maintenance.

Training and techniques provided: This project will involve integrated and iterative use of computational approaches to study cis-regulatory networks. Initial work will involve mutational mapping, followed by later bioinformatics approaches to integrating and interpreting findings. Validation work will provide training in cell culture, advanced molecular biology techniques, genome-wide sequencing based assays and basic biochemistry for protein purification.

Eligibility

Applicants are expected to hold (or about to obtain) a minimum upper second class undergraduate honours degree (or equivalent) in molecular biology, genetics, biochemistry, bioinformatics (and related areas). Additional masters level training in a complementary area to the degree programme is desirable. Direct experience in both lab-based research and computational approaches is desirable.

Application Guidance

We strongly recommend that you contact the project supervisor Andrew Sharrocks for this project before you apply. Please include details of your current level of study, academic background and any relevant experience and include a paragraph about your motivation to study this PhD project.

Apply directly via this link: OAA Applicant Portal or on the online application portal, select PhD Molecular Biology as the programme of study.

Please ensure that your application includes all required supporting documents: Curriculum Vitae (CV), Supporting Statement, Academic Certificates and Transcripts.

Incomplete or late applications will not be considered.