GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers

Craig H Mermel,Rameen Beroukhim,Steven E Schumacher,Gad Getz,Matthew L Meyerson,Barbara Hill

doi:10.1186/gb-2011-12-4-r41

Craig H Mermel, Rameen Beroukhim + Show 4 more

Open Access

https://doi.org/10.1186/gb-2011-12-4-r41

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Journal: Genome Biology	Publication Date: Apr 1, 2011
Citations: 2610	License type: CC BY 2.0

Affiliation: Dana-Farber Cancer Institute, Broad Institute

Abstract

We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets.

Highlights

Cancer forms through the stepwise acquisition of somatic genetic alterations, including point mutations, copy-number changes, and fusion events, that affect the function of critical genes regulating cellular growth and survival [1]
Step 3: Scoring somatic copy number alteration (SCNA) in each region according to likelihood of occuring by chance
The following sections describe improvements to steps 2 to 5. We evaluate these improvements on a test set of 178 glioblastoma multiforme (GBM) cancer DNAs hybridized to the Affymetrix Single Nucleotide Polymorphism (SNP) 6.0 array as part of The Cancer Genome Atlas (TCGA) project [10], and on simulated data

Summary

Introduction

Cancer forms through the stepwise acquisition of somatic genetic alterations, including point mutations, copy-number changes, and fusion events, that affect the function of critical genes regulating cellular growth and survival [1]. The identification of oncogenes and tumor suppressor genes being targeted by these alterations has greatly accelerated progress in both the understanding of cancer pathogenesis and the identification of novel therapeutic vulnerabilities [2]. Genes targeted by somatic copy-number alterations (SCNAs), in particular, play central roles in oncogenesis and cancer therapy [3]. Dramatic improvements in both array and sequencing platforms have enabled increasingly high-resolution characterization of the SCNAs present in thousands of cancer genomes [4,5,6]. Neutral or weakly deleterious ‘passenger’ alterations may become fixed whenever a

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