Abstract 1937: In-depth genomic analysis reveals complex functional consequence of driver mutations in breast cancers

Abstract

Abstract Understanding the extensive functional consequences of molecular drivers of a cancer is challenging. We developed an in-depth genomic analytical framework to identify the gene and pathway targets dysregulated by somatic driver mutations. Using The Cancer Genome Atlas (TCGA) breast cancer data, we systemically analyzed all high frequent mutation events including amplification, deletion and point mutation across tumor tissues. Those include the known molecular driver genes such as PIK3CA, GATA3, PTEN and TP53. Utilizing bagging with distance-based regression for differential gene expression analysis, we identified several thousands gene targets associated with the somatic mutations. Integrating gene co-expression regulatory network and the association dependence structure among the somatic mutations, we explored a complex association network of molecular pathway modules or sub-modules that are specific to a mutational event or common to a set of events. Interestingly, we found those modules commonly associated with sets of mutation events were significantly enriched in well-known breast cancer related pathways such as ERBB2, PI3AK and TGFB1. Combined with the publicly available data of a genome-wide RNA-mediated interference screen in breast cancer, we further demonstrated that those modules enriched with cell proliferation essential genes. Our analysis strategy provides a novel view of complex functional mechanism driven by the driver mutation events and it has high potential to provide novel insights to the understanding of the tumorigenesis or the development of therapeutic targets. Citation Format: Yaomin Xu, Xingyi Guo, Shilin Zhao, Eric Torstenson, Todd Edwards, Yu Shyr. In-depth genomic analysis reveals complex functional consequence of driver mutations in breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1937. doi:10.1158/1538-7445.AM2015-1937