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Open Access Highly Accessed Research

Copy number polymorphisms and anticancer pharmacogenomics

Eric R Gamazon1, R Stephanie Huang2, M Eileen Dolan2* and Nancy J Cox13*

Author Affiliations

1 Section of Genetic Medicine, Department of Medicine, University of Chicago, 900 East 57th Street, Chicago, IL 60637, USA

2 Section of Hematology/Oncology, Department of Medicine, University of Chicago, 900 East 57th Street, Chicago, IL 60637, USA

3 Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 5th floor, Chicago, IL 60637, USA

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Genome Biology 2011, 12:R46  doi:10.1186/gb-2011-12-5-r46

Published: 25 May 2011

Abstract

Background

Recent studies have investigated the contribution of copy number variants (CNVs) to disease susceptibility in a multitude of complex disorders, including systemic lupus erythematosus, Crohn's disease, and various neurodevelopmental disorders. Relatively few CNV studies, however, have been conducted on pharmacologic phenotypes even though these structural variants are likely to play an important role. We developed a genome-wide method to identify CNVs that contribute to heterogeneity in drug response, focusing on drugs that are widely used in anticancer treatment regimens.

Results

We conducted a comprehensive genome-wide study of CNVs from population-scale array-based and sequencing-based surveys by analyzing their effect on cellular sensitivity to platinating agents and topoisomerase II inhibitors. We identified extensive CNV regions associated with cellular sensitivity to functionally diverse chemotherapeutics, supporting the hypothesis that variation in copy number contributes to variation in drug response. Interestingly, although single nucleotide polymorphisms (SNPs) tag some of the CNVs associated with drug sensitivity, several of the most significant CNV-drug associations are independent of SNPs; consequently, they represent genetic variations that have not been previously interrogated by SNP studies of pharmacologic phenotypes.

Conclusions

Our findings demonstrate that pharmacogenomic studies may greatly benefit from the study of CNVs as expression quantitative trait loci, thus contributing broadly to our understanding of the complex traits genetics of CNVs. We also extend our PACdb resource, a database that makes available to the scientific community relationships between genetic variation, gene expression, and sensitivity to various drugs in cell-based models.