Abstract 4939: A characterization of pathway aberrations across human cancers
Authors: Antti Ylipää, Wei Zhang, Matti Nykter
Journal: Cancer Research (2012)

Abstract The development of cancer is driven by the acquisition of somatic genetic mutations, which provide cancer cells a selective advantage by altering biochemical pathways in various ways. Recent cancer genomics databases have made vast amounts of tumor characterization data available for the scientific community. These data, in combination with pathway databases and statistical computing, can be used to infer the aberrant pathways in each individual tumor. Identification and comparison of these pathways can provide insights into emergence and progression of cancer, and suggest potential therapeutic strategies. In this study, we investigate the degree of pathway alterations in multiple human cancers based on microarray expression data and an ensemble of pathways derived from various databases. By studying a sufficiently large collection of tumor samples, we aim to create a comprehensive catalogue of consistently altered pathways in each cancer. We first obtained all the gene expression data from cancers that have been characterized by The Cancer Genome Atlas project. Then, we downloaded pathway data from several pathway databases, totaling over 2500 unique signaling or metabolic pathways, gene sets, or gene categories. The pathways were combined into a compatible form by re-mapping the identifiers to official symbols. We computed gene set enrichment scores for each of the 1994 pathways of suitable size in each sample across all tumor types. The scores within each cancer type were first investigated to identify any putative functional subtypes, and then merged to produce a pathway level portrait of the disease. The pathway enrichment frequency profiles of all the tumor types were markedly uniform: categories such as cell-cell adhesion and immune response were the most frequently enriched in all tumor types. However, within many frequently altered pathways, the particular set of genes whose expression differences induced the significant enrichment scores varied notably. These instances may represent mutually exclusive mechanisms to alter the function of a pathway towards a similar endpoint. We also identified several pathways that were altered very frequently within a cancer type and rarely in other types of cancer. These pathways can give rise to the observed differences in physiological and phenotypic properties across cancers. Following large multi-institutional efforts to map cancer genomes, this study represents an attempt to extend the current genomic characterizations towards comparative and pathway level descriptions across the whole cancer family. In our study, many cancer types were represented by relatively few samples and others by none; therefore, further efforts will be needed to fully paint the landscape of aberrant pathways. Importantly, however, we were already able to provide a vast number of functional hypotheses that remain to be experimentally validated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4939. doi:1538-7445.AM2012-4939