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

Abstract

A B S T R A C TTargeted 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 diseasefocused gene panels to support discovery related to etiology. With validation, BCScreen may also be useful for toxicological screening relevant to breast carcinogenesis.

Integration of data across toxicity endpoints for improved safety assessment of chemicals: the example of carcinogenicity assessment

“…Fingerprints including biomarkers related to DNA, epigenetic, proteins and adducts can describe more directly mechanisms of carcinogenicity initiated by the exposure to environmental chemicals, thereby strengthening biological plausibility. They can also be applied to traditional epidemiological studies and be used as trackers to identify specific type of cancers (Ceccaroli et al 2015 ; Grashow et al 2018 ; Madia et al 2019 ). In our hypothesis, we consider that three main toxicity endpoints such as toxicokinetics, skin sensitisation and genotoxicity may be supplemented with the inclusion of information for ED mode of action, ToxCast, EpigeneticTox, and human information for biomarkers and SNPs and susceptibility factors for cancer disease (Fig.…”

Carcinogenicity assessment: Addressing the challenges of cancer and chemicals in the environment

“…Furthermore, biomarker gene signatures currently in use for early cancer diagnosis and clinical treatment decisions can be exploited to prioritise chemicals in need of thorough assessment for a specific cancer type. Grashow and co-workers (Grashow et al, 2018) have recently proposed an example of this type of approach. The authors have identified several occupational and environmental chemical classes that increase breast cancer risk.…”

“…However, thousands of chemicals remain untested for their breast carcinogenic potential. Therefore, the authors have used biomarker gene kits from clinics to prioritise and curate a panel of genes which can serve as a biomarker of mammary toxicity and breast carcinogenesis (Grashow et al, 2018; Rodgers et al, 2018).…”

“…The actual applicability of the options provided above is supported by a series of recent studies to evaluate chemicals for their potential to contribute to breast cancer risk (Grashow et al, 2018; Rodgers et al, 2018; Rudel et al, 2011; Schwarzman et al, 2015).…”

“…Starting from insights on the breast cancer aetiology and epidemiology evidence, a detailed analysis of biological effects of the disease and changes in biological pathways that serve as early indicators of toxicity has led to the development of tailored mechanistic tools able to identify specific breast cancer-inducing traits. Such new tools, such as the curated genomic biomarker panel for screening (Grashow et al, 2018) or the protocol for hazard identification (Schwarzman et al, 2015) can be fully integrated in the process of carcinogenicity assessment.…”