Detection of blood TCR signatures associated with risk and precursors of high-grade serous ovarian cancer (HGSOC)
Primary supervisor: Filipe Correia Martins, UCL
Secondary supervisor: Aleksandra Gentry-Maharaj, UCL
Project
Challenge
HGSOC is the most common and lethal form of ovarian cancer (OC) and is driven by extreme chromosomal instability in a background of mutant TP53(1). Its pre-cancerous precursor lesions in the fallopian tubes (FTs) already denote significant genomic complexity with chromosomal re-arrangements(2-4). Women who are predisposed to develop HGSOC due to pathogenic alterations in BRCA1/2 genes are currently offered risk reduction surgery with removal of FTs (+/- ovaries). In the general population, imaging and blood biomarkers allow the detection of HGSOC at early cancer stages but this does not significantly improve mortality rates(5). Strategies for detection of patients at higher risk of developing HGSOC (both BRCA and non-BRCA-related), who can be offered risk reduction procedures and new prevention clinical trials, remains a clinical research priority.
Preliminary data (confidential until end of 2025; manuscript in preparation):
We previously analysed the expression profiles from ~170k cells derived from 55 FT samples (both from BRCA1/2 mutation carriers and low-risk controls) and identified a population of secretory epithelial cells with high expression of TP53 (“TP53- high” cells) and cell proliferation markers, which undergo cell death in the G1/S cell cycle phase. Healthy low-risk controls show variable number of “TP53-high” cells, suggesting different levels of chromosomal instability in their epithelia and variable overall HGSOC risk. The proportion of proliferative TP53-high cells is increased in carriers of BRCA1/2 pathogenic alterations and correlates with the number of TREM2 macrophages, NK cells and CD8 T cells in the FTs. We have therefore hypothesized that presence of specific T-cell clones would be associated with the presence of “TP53-high” cells and that we could identify their presence in the blood.
Aim 1. Identification of T-cell clone signatures associated with chromosomal unstable cells
Research question: Do individual T-cell receptor(TCR)-specific CD8- and CD4-T cells clones correlate with the presence of chromosomally unstable epithelial cells (identified by high TP53 expression)?
1.1. Estimate of the proportion of proliferating “TP53-high” secretory epithelial cells that undergo cell death as well as of CD8 T cells, macrophages and NK cells from FT samples.
1.2 Identification and quantification of specific TCR-specific CD8- and CD4- T-cell subclones in the tissues.
Aim 2. Identification of T-cell clone signatures from the tissue in the blood.
Research question: Can FT tissue-specific TCR clones be detected in the blood?
WP. 2.1. Identification of individual TCR-specific CD8- and CD4-T cell clones in the circulation
WP. 2.2. Correlation between prevalence of tissue- and blood-derived individual TCR-clones.
Aim 3. Comparison T-cell clone signatures between high-risk genetic (eg. BRCA-associated) and low-risk samples
Research question: Are TCR-specific CD8- and CD4-T cell clones in blood and tissue different in high-risk genetic and low risk participants?
References
- Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast RC, Jr., Beral V, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer. 2015;15(11):668-79.
- Labidi-Galy SI, Papp E, Hallberg D, Niknafs N, Adleff V, Noe M, et al. High grade serous ovarian carcinomas originate in the fallopian tube. Nat Commun. 2017;8(1):1093.
- Ducie J, Dao F, Considine M, Olvera N, Shaw PA, Kurman RJ, et al. Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma. Nat Commun. 2017;8(1):990.
- Karst AM, Levanon K, Drapkin R. Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proc Natl Acad Sci U S A. 2011;108(18):7547-52.
- Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. Ovarian cancer screening and mortality in the UK Collaborafve Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;387(10022):945-56.