Abstract

An important goal of cancer genomic research is to identify the driving pathways underlying disease mechanisms. It is well known that somatic genome alterations (SGAs) affecting the genes that encode the proteins within a common signaling pathway exhibit mutual exclusivity, in which these SGAs usually do not co-occur in a tumor. With some success, this property has been utilized as an objective function to guide the search for driver mutations. However, the mutual exclusivity alone is not sufficient to indicate that genes affected by such SGAs are in common pathways. Here, we propose a novel, signal-oriented framework for identifying driver SGAs, such that our new method constrains the mutual exclusivity only on tumors that have SGAs to perturb a common signal (not on all tumors as previous methods used). We apply this framework to the OV and GBM data FROM TCGA, and perform systematic evaluations. Our results indicate that the signal-oriented approach enhances the ability to find informative sets of driver SGAs that likely constitute signaling pathways.

Highlights

  • Somatic genome alterations (SGAs) such as somatic mutations, somatic copy number alterations and epigenomic alterations are major causes of cancers[1,2,3]

  • We present a framework for discovering perturbed signaling pathways in cancers by integrating genome alteration data and transcriptomic data from the Cancer Genome Atlas (TCGA) project

  • somatic genomic alterations (SGAs) in a tumor can be divided into two types: those that affect cellular signaling proteins, perturb the cellular signaling system, and eventually contribute to cancer initiation and progression are called driver SGAs; and those that do not directly contribute to cancer development are designated as passenger SGAs

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Summary

Introduction

Somatic genome alterations (SGAs) such as somatic mutations, somatic copy number alterations and epigenomic alterations are major causes of cancers[1,2,3]. SGAs in a tumor can be divided into two types: those that affect cellular signaling proteins, perturb the cellular signaling system, and eventually contribute to cancer initiation and progression are called driver SGAs; and those that do not directly contribute to cancer development are designated as passenger SGAs. A fundamental problem of cancer-genome research is to identify signaling pathways that, when perturbed by driver SGAs, lead to cancer development or affect clinical outcomes for patients. A fundamental problem of cancer-genome research is to identify signaling pathways that, when perturbed by driver SGAs, lead to cancer development or affect clinical outcomes for patients Identification of such pathways will advance our understanding of the disease mechanisms underlying cancer, but will provide guidance for the precision treatment of cancer patients. By simultaneously capturing SGAs and gene expression data from each tumor, the TCGA data reflect the cause and readout of perturbed signaling pathways, providing a unique opportunity for studying cancer pathways

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