Translational Oncogenomics

We hope to understand how somatic genetic changes and TME effects proportionally increase aggressive clonal evolution and resistance in localised prostate and penile cancer phenotypes.  These factors may drive the genetic evolution in hereditary prostate cancers with BRCA2, ATM and MSH2 mutations (i.e. DDR deficient = “DDRd”) when compared to sporadic prostate cancers. Importantly, the outcomes are poor for 10-15% of high-risk localised prostate cancer patients who have these DDR germline defects. In these germline-associated DDRd mutations and prostate cancers, genetic instability is increased when compared to age-matched sporadic cancers and show behaviours that usually only occur in sporadic metastatic castrate resistant prostate cancer (mCRPC). drive new treatment options.

We have developed a translational pipeline to acquire normal and tumour tissues derived from gDDRd patients attending the DDR Urology clinic at the Christie NHS Foundation Trust. Patient-derived prostate epithelial cells (PrECs) have stable genomes and the ability to form 3D prostaspheres ex vivo.  We also have access to Europe’s largest collection of penile cancer cases married to clinical outcome for multiomic studies of genomic and TME changes in relation to HPV subtype and differential histopathology.

In general, we are  interested whether polyclonality arises from a functional loss of DDR, DNA replication fork stress and protection (c-Myc)  and/or loss of cell cycle arrest (loss of TP53 or RB), and how hypoxia may modify these evolutionary processes, in both prostate and penile cancers.

Objectives:

• Evolution of Polyclonality in Cancer uses whole genome sequencing of high-risk prostate cancers and develops novel human primary epithelial cell (PrEC) isogenic cells that represent sporadic and DDRd prostate cancer models. We determine cell autonomous effects of primary and secondary somatic mutations and TME-hypoxia effects on DNA replicative stress and the absence of cell cycle checkpoints. In penile cancer, we also study HPV-subtypes and HPV programming in a similar context.
• Tumour Architecture of Aggression will define polyclonality and evotypes in hypoxic sub-regions of sporadic and hereditary prostate primary tumours and metastases and primary penile tumours using spatial multiomics relative to in situ genomic alterations. It will define polyclonality and secondary somatic mutations in situ in the context of hypoxic sub-regions, CIN/replication stress and immune cell infiltration.
• Mapping Resistance Phenotypes uses sporadic and hereditary  tumour models (PrEC, DVL3, LnCaP) to test whether de novo or acquired polyclonality leads to differential Enzalutamide resistance (EnzaR) or DDR inhibitor resistance.