Shared genetics between breast cancer and its predisposing diseases identify novel breast cancer treatment candidates

Abstract

Breast cancer is a major public health issue. Current treatment options, while effective, have severe side effects. FDA-approved drugs have known safety and pharmacological profiles and some, such as metformin, have been tested in clinical trials for repurposing for breast cancer. However, clinical trials are slow and expensive, which creates the need for innovative approaches to accelerate drug repurposing for breast cancer. We have previously shown that genes associated with Mendelian diseases that predispose patients to certain cancers are enriched for successful drug targets, due to their pleiotropic effects. Here, we extend our approach to exploit clinical associations between breast cancer and its predisposing diseases for drug repurposing. We hypothesize that pleiotropic genes shared between breast cancer and its predisposing diseases can help us discover new uses for drugs currently approved only for the predisposing diseases. To test our hypothesis, we compile a list of six traits known to increase breast cancer risk (predisposing diseases). Using GWAS summary statistics and local genetic correlation analysis, we find 84 genomic loci harboring mutations with positively correlated effects between breast cancer and each predisposing disease. These loci contain 194 protein-coding genes (shared genes). Using a network biology approach and canonical pathways, for each disease pair, we connect drugs already indicated for the predisposing disease to its shared biology with breast cancer and identify drug repurposing candidates for breast cancer. Finally, we show that our list of candidate drugs is enriched for currently investigated and indicated drugs for breast cancer (OR=9.28, p=7.99e-03). Our findings suggest a novel way to accelerate drug repurposing for complex diseases by leveraging shared genetics.