Beyond BRCA1/2: dissecting drivers of chromosome instability in high-grade serous ovarian cancer

Project Outline

High-grade serous ovarian cancer (HGSOC), the commonest OC histological subtype, is a lethal disease, with a 5-year survival of ~30% for women presenting with advanced-stage disease. The molecular hallmark of HGSOC is a highly disordered genome, consistent with rampant chromosomal instability (CIN), where complex structural variants (e.g., large deletions, duplications, insertions, translocations) occur throughout the tumour genome. Indeed, CIN is associated with the prevalence of metastatic disease and chemotherapy-resistance, although crucially, the oncogenic drivers of HGSOC-specific CIN are poorly understood. 

Approximately 20% of patients with HGSOC have an inherited loss-of-function mutation that predisposes them to developing cancer. The commonest genes linked to hereditary HGSOC are BRCA1/2, although mutations in rarer genes such as BRIP1, PALB2, RAD51C/D also substantially increase the risk. These genes are involved in homologous recombination (HR), a high-fidelity DNA double-strand break repair pathway that maintains chromosomal stability. Importantly, the rarity of HGSOCs harbouring a germline non-BRCA1/2 HR gene mutation (~5%) hinders our understanding of their influence on CIN and impairs our ability to predict responses to highly effective targeted poly(ADP-ribose) polymerase inhibitors (PARPi). 

This project aims to understand the relationship between mutations in non-BRCA1/2 HR genes, CIN and PARPi sensitivity. Experimental models with loss-of-function mutations in BRIP1, PALB2, RAD51C/D will be generated using CRISPR/Cas9 technology in fallopian tube epithelial cells, a precursor of HGSOC. Each model will be interrogated for HR-deficiency and PARPi sensitivity using cell-based assays, whilst concurrent whole-genome and RNA sequencing will be performed to discover consequential acquired patterns of CIN. Finally, whole-genome data and PARPi responses from patients treated for HGSOC at The Christie will be assessed to validate the veracity of these models. 

Altogether, the Fellow will learn a comprehensive set of wet-lab and bioinformatic skills, taught by an expert team of clinicians and scientists, in a highly collaborative, translationally focussed, state-of-the-art lab. 

Applications for this project are now open. Please complete your application on The University of Manchester website.