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Barts Cancer Institute funded PhD: Elucidate the Role Of MMR Loss in Endometrial Cancer Metastasis

  • Full or part time
  • Application Deadline
    Tuesday, January 01, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

We are pleased to offer a fully funded PhD studentship starting in March 2019.

Our research training programme aims to develop a cohort of scientists equipped both intellectually and technically to conduct the highest quality cancer research.

Our research degrees are supplemented by a comprehensive support programme, providing training in a wide range of biomedical laboratory methods and other vital transferable skills.

Project outline:
Endometrial cancer (EC) is the 4th most common cancer in women and the most common gynaecological malignancy in the developed world. Although approximately 75% of patients present with early stage disease, 15-20% of these tumours recur after primary surgery. Outcomes for women with advanced or recurrent disease are extremely poor and the median survival in metastatic disease is only 7-12 months. Loss of the DNA mismatch repair pathway (MMR) is estimated to occur in approximately 30% of endometrial tumours. Whilst a small proportion of these are due to germline defects in one of the four MMR genes (MLH1, MSH2, MSH6 and PMS2), most result from epigenetic loss of MLH1. MMR deficiency is associated with well-established poor prognostic indicators in many studies of endometrioid EC, including high tumour grade, lymph node involvement, metastasis and recurrence. It has also been shown that that epigenetic MMR loss confers a worse prognosis than germline MMR loss. Currently, we do not know why this is the case and how this may impact on treatment approaches and survival outcome.

In this PhD studentship, we will dissect for the first time the specific molecular changes that occur in EC cells upon loss of function MLH1 mutation versus MLH1 methylation. To this end, we will use state-of-the-art CRISPR/Cas9 gene editing tools to directly mutate or methylate MLH1 in MMR-proficient normal primary endometrial cells. Using these models, we will determine whether mutation or methylation of MLH1 changes the ability of cells to metastasize. The MLH1mut and the MLH1meth cells will be analysed by whole-exome and RNA sequencing, to determine whether mutation or epigenetic loss of MLH1 leads to different mutator phenotypes and activation of distinct transcriptional programs.

For more information, please see:

Funding Notes

The studentship includes the following funding for 3 years:
- A tax free annual stipend of £21,000
- Tuition Fees at the Home/EU rate*
- Project consumables

*If you are considered an overseas student for fee purposes, you are welcome to apply for this studentship, however you will be required to cover the difference in tuition fees.

How good is research at Queen Mary University of London in Clinical Medicine?

FTE Category A staff submitted: 144.11

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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