Identification and characterisation of a genetic signature at the 5p15 region associated with prostate cancer across ethnic groups
Genome-wide association studies (GWAS) which assess thousands of single nucleotide polymorphisms (SNPs) in large cohorts have provided new insights into the genomic regions that alter an individual’s risk of developing a disease and have been implicated in clinics. In a study in Australian males, we have recently replicated the association of a novel rs12653946 SNP at 5p15 identified through a Japanese study. In addition, our preliminary analysis of the RNAseq and microarray data supports the role of at least two genes of interest at this prostate cancer locus - the novel gene Hurey, and hormone-regulated gene IRX4.
We now propose to undertake the fine mapping and functional studies to determine the causal SNP/s and the gene/s at this locus, for future risk prediction modelling for prostate cancer. For the fine-mapping, our large sample of 3100 cases and 1500 controls will genotyped using the Sequenom Massarray after extracting data from the 1000 genomes project and through COGS (the Collaborative Oncological Gene-Environment Study). Risk associated SNPs in the genes at 5p15 will be validated via the largest prostate cancer consortium (PRACTICAL).
Our approach will focus on the molecular phenotypes of association findings and functional characterization of the plausible causal gene and its variants using various in vitro methods established in our laboratory in order to understand how common sequence variation/s in prostate cancer risk associated genes at 5p15 plays a role in the development of cancer. Biological insights can then be translated to clinical benefits, including reliable biomarkers and effective strategies for screening and disease prevention.
