Abstract LB-C04: Modeling the impact of somatic alterations across human cancers

Abstract

Abstract Modeling the impact of somatic alterations across human cancers Hatice U. Osmanbeyoglu1, Christina S. Leslie1,* 1Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY Abstract Large-scale cancer genomics projects like The Cancer Genome Atlas have generated a comprehensive catalog of somatic mutations and copy number aberrations across many tumor types, but the role of some frequently altered genes remains obscure. To better model the impact of these alterations, we developed a computational strategy for exploiting parallel phosphoproteomics and mRNA sequencing data for large tumor sets to link dysregulation of upstream signaling pathways with altered transcriptional response through the transcriptional circuitry. Our modeling allows us to interpret the impact of mutations and copy number events in terms of altered signaling and transcription factor (TF) activity. We used a novel machine learning strategy to train phosphoprotein-TF interaction models across 10 human cancers for which large reverse-phase protein array and RNA-seq data sets are available through TCGA. We then applied a novel algorithmic approach to extract networks of signaling proteins and TFs whose inferred activities are correlated across tumors and whose dysregulation is associated with specific somatically altered genes. Our analysis revealed both known and novel interactions of frequently altered genes with signaling pathways and transcriptional programs in a pan-cancer context. Moreover, our algorithmic approach provides a general strategy for modeling the impact of recurrent mutations and copy number alterations on signaling pathways and transcriptional programs through pan-cancer analysis. Citation Format: Hatice U. Osmanbeyoglu, Christina Leslie. Modeling the impact of somatic alterations across human cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C04.