Background

Sex disparities have been frequently observed in most tumours of non-reproductive tissues, with both incidence and mortality rates being higher in males. There are many factors contributing to such differences, including differences in physiology, effect of sex hormones, environmental exposure and behaviour, and genetics of sex chromosomes. Loss of Y chromosome (LOY) has been identified as a frequent event, occurring in ~30% of >5,000 TCGA male tumours across cancer types. Tumours with LOY seemed to have poorer prognoses compared to wildtype tumours in many cancers, such as bladder, prostate cancer, uveal melanoma and mesothelioma. However, the extent of LOY, its clinical significance and functional impact on tumour progression are still unknown in cutaneous and oral squamous cell carcinoma (cSCC and OSCC).

In both cSCC and OSCC, the disease incidence is much higher in males than in females, with ~2.5-4:1 incidence ratio on average across different populations. Male patients are more likely to have aggressive tumours and develop metastasis. In this project, we will utilise matched whole-exome sequencing (WES), RNA-seq and digital pathology data of publicly available and in-house cohorts, and systematically investigate the clinical and biological significance of LOY in cSCC and OSCC using integrated multi-omics strategy.

Hypothesis

LOY is frequent in SCC and is associated with disease progression and metastasis. Tumour cells with LOY dysregulate immune microenvironment that may provide cues for improved immunotherapy.

Aims

1. Reveal the frequency of male tumours with LOY in cSCC and OSCC. Previously published and in-house cSCC and OSCC cohorts and samples will be used to confirm LOY prevalence in SCC and also in pre-malignant tissues. We will perform clonality analysis, associate LOY with other driver mutations, such as TP53, NOTCH1/2, CDKN2A and FAT1, and identify potential driver candidates on chromosome Y.
2. Identify the association between LOY and clinical outcomes. We will assess LOY with known clinical outcomes in our cohorts, including metastasis-free survival, cancer staging and differentiation status. We will also investigate how frequency of samples with LOY changes with disease progression and stages.
3. Identify gene signatures and dysregulated pathways associated with LOY compared to wildtype tumours using matched RNA-seq data. LOY specific gene signatures will be derived for samples without WES data to detect LOY.
4. Investigate the interaction between LOY cancer cells and their microenvironment using spatial techniques, such as 10x Visium HD, PhenoCycler and Cell Dive (e.g., 6 LOY vs. 6 wildtype tumours). The interacted immune/stroma cells and novel ligand-receptor links associated with LOY tumour cells will be identified.
5. Develop a deep-learning resource to analyse digitised H&E whole slide images and identify LOY tumours and their associated histopathological features.

Students will be trained with cutting-edge omics, single-cell and spatial techniques and embedded within highly translational research environment. The research will have the access to the support of core facilities at Barts Cancer Institute, Blizard Institute and Barts Centre for Squamous Cancer.

Academic Entry Requirements

All applicants should have or be expecting:

• A first or upper second class honours degree in a relevant biological subject from a UK university or the international equivalent from a recognised institution, or
• A medical degree from a recognised institution.

This project would suit candidates with a background in genomics and bioinformatics and an interest in cancer genomics, spatial biology, digital pathology and sex disparities in cancer.

English Language Requirements

Applicants for whom English is not a first language will also require a minimum IELTS score of 6.5 (with 6.0 in the written component) or equivalent, unless your undergraduate degree was studied in, and awarded by, an English speaking country. For more information on acceptable English language qualifications please see here.

Fee Status

The funding for this studentship only covers tuition fees at the Home rate. Overseas applicants are welcome to apply but will be required to fund the difference in tuition fees.

The studentship includes the following funding for 4 years:

• A tax-free annual stipend at the UKRI rate
• Tuition fees at the Home 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.

To apply you will need to complete an online application form. Please select the 'Non-Clinical PhD' option.

The following supporting documents will be required as part of your application:

• Your CV
• Statement of purpose
• Details of 2 referees
• Copy of your transcript(s), including a breakdown of marks
• Copy of your passport
• If applicable, proof of English proficiency

If you have a question about the project, or would like to arrange an informal discussion, please contact the supervisor directly (subject ‘PhD applicant’). For general enquiries about the PhD studentship or application process please contact the Teaching Office.

Successfully shortlisted candidates will be invited to an interview at Barts Cancer Institute.