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(MRC DTP) Genomic drivers and mechanisms of colorectal peritoneal metastasis formation


   Faculty of Biology, Medicine and Health

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  Prof David Wedge, Prof Omer Aziz, Prof Sarah O'Dwyer, Prof C Yau  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Over 40,000 patients are diagnosed with colorectal cancer every year in the UK. Unfortunately 40% die within 5 years with metastatic disease to the liver, lungs, and peritoneum (lining of the abdomen). Colo-Rectal Peritoneal Metastases (CRPM) affect up to 20% of patients and have significantly reduced median overall survival (16.3 months) compared to liver (19.1 months) and lung metastases (24.6 months).

We have recently developed a ‘peritoneal signature’, identified through the PanCancer 360 Gene Expression Panel, which has been applied and tested on transcriptomic data from large worldwide consortia, identifying deregulated pathways that suggest peritoneal metastasis may be a relatively early event to develop in this patient group1. However, relatively little is known about the genetic drivers of CRPM. In this study, we will collect tissue samples from 50 CRPMs and from the matched primary tumours, and perform whole genome sequencing (WGS) in order to identify the full range of genomic aberrations that have occurred in the cancer cells, including large structural rearrangements, copy number aberrations, small insertions/deletions and single nucleotide variants (SNVs). By comparing the mutations found in the primary and metastatic lesions, we will identify the likely genetic drivers of CRPM. We also aim to elucidate the process of metastasis, for example discovering whether CRPMs grow from a single cell (monoclonal seeding) or are derived from multiple cells with different genotypes (polyclonal seeding).2

The supervisory team for this project is led by an expert in Cancer Genomics and Data Science, who has pioneered many of the analytical methods used to study cancer evolution, and the mechanism and process of metastasis3,4. Additional supervisors are academic clinicians from the Colorectal and Peritoneal Oncology Centre (CPOC) research group based at Academy of Surgical Oncology, The Christie Hospital and the Manchester Cancer Research Centre. CPOC is a high volume national peritoneal tumour service which treats over 50 CRPM patients/year using specialised cytroreductive surgery (CRS) techniques and hyperthermic intraperitoneal chemotherapy (HIPEC).

This project involves no wet-lab work and would be suitable for a student with working knowledge of cancer genomics and/or strong skills in bioinformatics/programming. They would be fully supported in further developing these skills and in applying them to the study of drivers and mechanisms underlying the formation of CRPMs. Integration within a clinical and academic team will allow rapid translational application of the knowledge gained from this study.

https://www.research.manchester.ac.uk/portal/david.wedge.html
https://wedge-group.netlify.app/
https://www.research.manchester.ac.uk/portal/omer.aziz.html
https://www.christie.nhs.uk/patients-and-visitors/services/colorectal-and-peritoneal-oncology-centre

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

References

1. Bhullar DS, Barriuso J, Mullamitha S, Saunders MP, O'Dwyer ST and Aziz O. Biomarker concordance between primary colorectal cancer and its metastases. EBioMedicine. 2019;40:363-374.
2. Gundem G, Van Loo P, Kremeyer B et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520(7547):353-7.
3. Nik-Zainal S, Van Loo P, Wedge DC et al. The life history of 21 breast cancers. Cell. 2012;149(5):994-1007.
4. Gerstung M, Jolly C, Leshchiner I et al. The evolutionary history of 2,658 cancers. Nature. 2020;578(7793):122-8.
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