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  Identify the carcinogen that causes oesophageal cancer


   Nuffield Department of Medicine

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  Dr Benjamin Schuster-Boeckler, Dr Francesco Boccellato, Prof Skirmantas Kriaucionis  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Gastro-oesophageal adenocarcinomas (GOAC) are characterised by a very high frequency of T to G mutations and chromosomal instability. We know from epidemiological data that reflux disease is a major risk factor for oesophageal cancer, and that bile reflux in particular seems to associate with an increased risk of gastric and oesophageal cancer. However, the causal mechanism by which acid and/or bile reflux cause mutations has not yet been identified. If we understood the molecular details of the process, it could open up new ways to chemically or behaviourally reduce the risk of developing this devastating disease.

The goal of this project is to understand the role of environmental influences and cell-type specific characteristics in the accumulation of mutations and chromosomal aberrations in the upper GI tract. We have recently established organoid models of the stomach epithelium. Based on these models, we have evidence to show that bile exposure is in fact mutagenic. We also identified a possible mechanistic link between reflux exposure and the characteristic T to G mutation pattern found in GOAC.

Going forward, there are multiple experimental and computational pathways we hope to explore further. We are performing mass-spectrometry and sequencing experiments to investigate the effect of different putative mutagens on DNA replication and the associated repair. Using existing public data, we hope to identify similarities between the molecular phenotypes observed in our in-vitro system to that observed in cancer patients. We also aim to further develop the in-vitro models by selectively inhibiting specific DNA repair processes to validate our mechanistic hypotheses regarding the molecular mechanism driving mutagenesis in GOAC.

This project would be an opportunity for an inquisitive young researcher who wants to solve a puzzle that so far has eluded resolution. To achieve it, you will require a good understanding of molecular biology. Beyond that, we can tailor the project to be more laboratory focussed or more computational. In the former case, you should have some experience with cell-culture, performing sequencing experiments and/or mass-spectrometry. In the latter case, you should have a solid background in a computational field, ideally with experience in genomics data analysis.

Please quote the project ID Ludwig and indicate the course code RD_CM1 in your application. Please use the project details above for your research proposal.

For entry requirements and to apply for this project please visit the University of Oxford DPhil in Clinical Medicine pages

If you plan to apply to more than one Ludwig studentship project, you may list a maximum of two of our projects on your application. 

Please note that only applicants who apply for a DPhil in Clinical Medicine via the University of Oxford admissions system will be shortlisted for interview.

Enquiries

Benjamin Schuster Boeckler ([Email Address Removed]) – project related enquiries

Alexandra Royer ([Email Address Removed]) – application related enquiries

Do not send your application to these email addresses, only applications submitted visa the University of Oxford admissions system will be considered

Application deadline closes Monday 1st April. Deadline for receipt of references: Friday 5th April.

Biological Sciences (4) Computer Science (8)

Funding Notes

The Ludwig Institute for Cancer Research studentships are for 4 years and provide an annual tax-free stipend of £21,000 and fees at the home or international rates.

References

• The Cancer Genome Atlas Research Network et al. Integrated genomic characterization of oesophageal carcinoma. Nature 541, 169-175 (2017).
• Tomkova, M., Tomek, J., Kriaucionis, S. & Schuster-Böckler, B. Mutational signature distribution varies with DNA replication timing and strand asymmetry. Genome Biology 19, 129 (2018)
• Christensen et al. 5-Fluorouracil Treatment Induces Characteristic T>G Mutations in Human Cancer. Nature Communications (2019): 1–11.