Investigation of loss of Y chromosome and its functional role in driving disease progression and immune evasion in cutaneous and oral squamous cell carcinoma

This CRUK Barts Cancer Bioinformatics Core funded project will commence in September 2025 and has funding for 4 years. 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. The successful candidate will be based at Barts Cancer Institute, Faculty of Medicine and Dentistry (FMD), Charterhouse Square in the City of London.

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.