- Suitable for PhD students only.
Our genome-wide association studies (GWAS) have identified 179 breast cancer risk loci. The functional mechanism behind the associations usually involves perturbed regulation of target gene transcription by risk-associated single nucleotide polymorphisms (SNPs) lying in regulatory elements positioned some distance from the target. We have developed a scoring system (integrated expression quantitative trait and in silico prediction of GWAS targets – INQUISIT) to rank the predicted target genes at breast cancer risk loci, based on multiple features from in-silico data in breast tissue. In total, we have identified 1648 candidate breast cancer risk genes, including 541 non-coding genes (mostly lncRNAs), and including HLA-A and several others which have been identified in a CRISPR screen for essential genes for melanoma immunotherapy. We therefore hypothesise that some breast cancer risk genes may act by affecting immunosurveillance, specifically the ability of the host to recognise and eliminate nascent tumours. To test the functionality of all 1648 candidate risk genes in T-cell mediated killing we will perform pooled clustered regularly interspaced short palindromic repeats (CRISPR) screens to systematically identify the relevant genes, and then determine whether the risk SNPs loop to, and moderate expression of, those genes to those found to be functionally relevant. This innovative project could eventually lead to novel immunoprevention strategies and synergistic immune checkpoint blockade and targeted therapy for breast cancer.
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