Abstract 392: Application of somatic mutation-based expression profiles for high-throughput phenotyping in cancer

Abstract

Abstract Somatic mutations have been heavily implicated in initiating and driving cancer growth and metastasis. These alterations serve as upstream events that have broad transcriptional effects by altering protein structure and function and interfering with signaling pathways. Here, we apply an iterative approach that utilizes patient gene expression profiles to define mutation-associated transcriptomic signatures. We use these signatures to quantify the level at which a given somatic mutation affects its gene’s downstream activities. Using TP53 in breast cancer as an example, we show that while TP53 mutations are the primary predictor of altered p53 activity, events such as copy number alterations and methylation changes may represent alternative routes to high p53 disruption. Conversely, we identify a class of TP53 mutations that have minimal downstream transcriptomic effects. By expanding this approach to other genes and tumor types, we show that mutation signatures derived from different tissue types exhibit varying levels of conservation, suggesting a degree of tissue-specificity in the downstream effects of somatic mutations. To provide functional context to our results, we examine the associations between different mutation signatures and various cancer-related features, including patient survival, immune infiltration, and pathway activity. Together, our results indicate the utility of using patient gene expression profiles to study mutation function. Going forward, these results may be useful in functionally annotating variants of unknown significance and broadening the potential of precision medicine-based therapeutic approaches. Citation Format: Frederick S. Varn, Yue Wang, Chao Cheng. Application of somatic mutation-based expression profiles for high-throughput phenotyping in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 392. doi:10.1158/1538-7445.AM2017-392