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WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

Genetic Instability and Aggression in Prostate Cancer

All solid tumours, including prostate cancer, contain sub-regions of dynamic changes in nutrient and oxygen metabolism. Hypoxia (low oxygen tension) leads to a number of aggressive tumour cell phenotypes and genetic instability, in part, driven by the down regulation of gene expression and translation of HR genes (Bristow and Hill, Nat Rev Can, 2005). This can drive a microenvironment-induced "BRCAness" leading to a contextual synthetic lethality and a way forward using treatments that target HR-defective hypoxic cells. This includes the potential use of the chemotherapy drug, cisplatin, or PARP inhibitors, similar to their use in prostate or other cancers that have genetic defects in BRCA1 or BRCA2 (Luoto et al; Genome Integrity 2013).

Recently, our group, in collaboration with scientists in Melbourne, have used whole genome sequencing (WGS) to explore the genetic defects in the tissues derived from untreated localised prostate cancers that arise in men with familial BRCA2 mutation carrier status (Taylor et al; Nature Comm, Jan 2017; Boutros et al; Nature, 2017) compared to those that arise as sporadic prostate cancers. 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.