This 4 year PhD studentship offered in Professor Rob Bristow’s research group is based at the Cancer Research UK Manchester Institute, Manchester Cancer Research Centre, Oglesby Cancer Research Building, Manchester
Defects in the repair of DNA replication errors and DNA double-stranded breaks have been associated with acquiring genetic instability. Genes responsible for mismatch repair (MMR) and homologous recombination (HR) such as BRCA1 and BRCA2. Defects in these genes lead to an increased risk of colorectal cancer (MMR or ovarian and breast cancer in women (BRCA1/2) or prostate cancer in men (MMR, BRCA2). BRCA2- associated prostate cancers have a particular poor outcome with more than 50% of men dead at 5 years after local therapy. Mismatch repair-deficient tumours may have improved outcomes with immunotherapy due to an increased mutation load.
Our group has used whole genome sequencing (WGS) to explore the genetic defects in the tissues derived from untreated localized prostate cancers that arise in men with familial BRCA2 mutation carrier status (Taylor et al; Nature Comm, Jan 2017; Boutros et al; Nature, 2017; Espiratu et a;; Cell, 2018)). We observed activation of a number of pathways usually reserved solely for patients that acquire castrate resistance and metastasis during the progression of sporadic cancer including altered beta catenin- WNT signalling, defective mitotic control and DNA repair and altered androgen signalling.
Together, these findings suggest that in untreated BRCA2-associated prostate cancers, pathways are already upregulated that herald resistance to hormone therapy and genetic instability. Subclonal analyses have revealed that IDCP and invasive adenocarcinoma in BRCA2-mutant tumours can arise from the same ancestral clone, implying that a temporal evolutionary trajectory exists. Finally, functional studies have shown that BRCA2-mutant tumours can harbour a subpopulation of cancer cells that can tolerate castration de novo, enabling the tumour to evade androgen deprivation therapy. Importantly, future challenges remain regarding how to best model the biology underpinning this aggressive phenotype and translate these findings to improve clinical outcomes (Taylor et al; Nat Rev Urol, 2019). Little is known regarding the role of MMR genes and relative prostate cancer aggression in patients with Lynch Syndrome.
The project will use whole genome and RNA sequencing in archival and flash-frozen primary human specimens of BRCA2mt and MMRmt prostate cancers to understand the role of acquired gene mutations, structural rearrangements and RNA splice variants in these tumours when compared to sporadic prostate cancers. Using in situ proteomic techniques, the cellular heterogeneity of these tumours will be characterised for epithelial, stromal and immune cell infiltration and interactions in oxic and hypoxic sub-regions. Information from these clinical studies will be used to formulate ex vivo models of progression using primary Tert-immortalised prostate epithelial cells which contain human-specific BRCA2, PALB2, ATM or MMR and oncogene/tumour suppressor gene mutations driven by CRISPER-Cas9 knock-out and knock-in technologies. These model cells will be used in 3D printed models co-cultured with stromal and immune cells to track genetic instability ex vivo and compare these pathways to the data accumulated from primary human tumour sequencing studies. Success in this project would outline a way forward to prevent additional genetic instability and resistance in hereditary forms of prostate cancer to improve patient outcomes.
Applications are invited from exceptionally high calibre students, graduates or final year undergraduates who should hold or are expected to gain a first/upper second-class honours degree in a relevant subject as part of a University degree course.
Applicants can find full group project details, entry criteria and details on how to apply online at: http://www.cruk.manchester.ac.uk/education/PhD-Studentships
Closing date: Friday 3 January 2020 – 2100 hours GMT
Interview date: Tuesday 18 February 2020, Alderley Park, Cheshire