Copy number polymorphisms and anticancer pharmacogenomics

Eric R. Gamazon, R. Stephanie Huang, M. Eileen Dolan, Nancy J. Cox

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Article numberR46
JournalGenome Biology
Issue number5
StatePublished - 2011

Bibliographical note

Funding Information:
This work was funded through Pharmacogenomics of Anticancer Agents Research (PAAR; U01 GM61393), ENDGAMe (ENhancing Development of Genome-wide Association Methods) initiative (U01 HL084715), the Genotype-Tissue Expression project (GTeX) (R01 MH090937), Rare Variants and Complex Human Phenotypes (U01HG005773), the University of Chicago Breast Cancer SPORE (P50 CA125183), Specialized Center of Research Grant from the Leukemia and Lymphoma Society and the University of Chicago DRTC (Diabetes Research and Training Center; P60 DK20595). RSH received support from NIH/NIGMS grant K08GM089941, NIH/NCI grant R21 CA139278, University of Chicago Cancer Center Support Grant (#P30 CA14599), and Breast Cancer SPORE Career Development Award. The authors are grateful to Anuar Konkashbaev and Wasim Bleibel for excellent technical assistance. We acknowledge the Wellcome Trust Case Control Consortium for making available data about SNP tagging of common CNVs [34].


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