P3-06-07: Integrated Genomic and Pathway Analysis Reveals Key Pathways across Breast Subtypes.
Authors: S Benz, JZ Sanborn, C Vaske
Journal: Cancer Research (2011)

Abstract Cancer is a disease of genomic perturbations that lead to dysregulation of multiple pathways within the cellular system. While common pathways are believed to be shared within specific cancer types, the mechanisms behind why particular patients respond differently to treatment is not well understood. Genomics studies such as The Cancer Genome Atlas (TCGA) and Stand Up To Cancer (SU2C) attempt to address this issue by collecting large-scale whole-genome measurements of mRNA expression, DNA copy number, and epigenetic features. Common analysis of these measurements integrates data across multiple samples to distinguish signal from noise. However, serious challenges remain in identifying genomic features and pathways significant for prognosis and clinical treatment classifications. We have created the Five3 Analysis Pipeline to streamline discovery of individual samples’ mutations, small indels, copy number alterations, genome rearrangements, expression changes, and resulting pathway activities. This pipeline is capable of processing and integrating data from both next generation sequencing and microarray platforms in the analysis of single or multiple tumor samples. Our sequence analysis corrects for both tumor sample impurity and germline variation to accurately identify somatic mutations present in the tumor. Our pathway analysis incorporates gene copy number, mutations, expression, and promoter methylation on a superimposed pathway constructed from several curated pathway databases in a sample-specific manner. By applying this pipeline to the TCGA breast cancer datasets, we recapitulate established breast subtypes at a pathway-dependent level. For example, basal tumors appear enriched for proliferation pathways compared to luminal samples within this cohort. Expanding the pathway analysis to include TCGA lung cancer samples, we find similar subnetworks activated between basal and squamous lung and between luminal and lung adenocarcinomas. This hints at similar genomic mechanisms for these subtypes independent of tissue of origin. Finally, by analyzing genomic alterations across all breast cancers we see mutational clusters in PIK3CA that correspond with publicly-available hotspots [1]. As suggested by previous reports [2], we find that samples with mutations clustered in exon 10 exhibit differential pathway activities relative to those samples with mutations clustered in exon 21, independent of subtype and TP53 mutation status. These results show the power of this integrated genomic platform in elucidating pathway signatures and the need to consider cross cancer analyses to identify shared tumorigenic mechanisms that may suggest common therapeutic targets. [1] Forbes, S.A et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucl. Acids Res. (2011) 39: D945-D950 [2] Vasudevan KM et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009 Jul.;16(1):21–32. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-06-07.