BCScreen: A gene panel to test for breast carcinogenesis in chemical safety screening

Targeted gene lists have been used in clinical settings to specify breast tumor type, and to predict breast cancer prognosis and response to treatment. Separately, panels have been curated to predict systemic toxicity and xenoestrogen activity as a part of chemical screening strategies. However, currently available panels do not specifically target biological processes relevant to breast development and carcinogenesis. We have developed a gene panel called the Breast Carcinogen Screen (BCScreen) as a tool to identify potential breast carcinogens and characterize mechanisms of toxicity. First, we used four seminal reviews to identify 14 key characteristics of breast carcinogenesis, such as apoptosis, immunomodulation, and genotoxicity. Then, using a hybrid data and knowledge-driven framework, we systematically combined information from whole transcriptome data from genomic databases, biomedical literature, the CTD chemical-gene interaction database, and primary literature review to generate a panel of 500 genes relevant to breast carcinogenesis. We used normalized pointwise mutual information (NPMI) to rank genes that frequently co-occurred with key characteristics in biomedical literature. We found that many genes identified for BCScreen were not included in prognostic breast cancer or systemic toxicity panels. For example, more than half of BCScreen genes were not included in the Tox21 S1500+ general toxicity gene list. Of the 230 that did overlap between the two panels, representation varied across characteristics of carcinogenesis ranging from 21% for genes associated with epigenetics to 82% for genes associated with xenobiotic metabolism. Enrichment analysis of BCScreen identified pathways and processes including response to steroid hormones, cancer, cell cycle, apoptosis, DNA damage and breast cancer. The biologically-based systematic approach to gene prioritization demonstrated here provides a flexible framework for creating disease-focused gene panels to support discovery related to etiology. With validation, BCScreen may also be useful for toxicological screening relevant to breast carcinogenesis.