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Research Articles: Targets

Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel

¹ Laboratory of Molecular Pharmacology and ² Genetics Branch, National Cancer Institute, Bethesda, Maryland; Departments of ³ Laboratory Medicine, ⁴ Anatomy, ⁵ Epidemiology and Biostatistics, and ⁶ Biopharmaceutical Sciences; ⁷ University of California San Francisco Comprehensive Cancer Center; ⁸ Cancer Research Institute, University of California San Francisco, San Francisco, California; and ⁹ Science Applications International Corporation-Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, Maryland

Requests for reprints: John N. Weinstein, Laboratory of Molecular Pharmacology, National Cancer Institute, Building 37, Room 5056, NIH, MSC 4255, 9000 Rockville Pike, Bethesda, MD 20892-4255. Phone: 301-496-9571; Fax: 301-402-0752. E-mail: weinstein{at}dtpax2.ncifcrf.gov

Abstract

Chromosome rearrangement, a hallmark of cancer, has profound effects on carcinogenesis and tumor phenotype. We used a panel of 60 human cancer cell lines (the NCI-60) as a model system to identify relationships among DNA copy number, mRNA expression level, and drug sensitivity. For each of 64 cancer-relevant genes, we calculated all 4,096 possible Pearson's correlation coefficients relating DNA copy number (assessed by comparative genomic hybridization using bacterial artificial chromosome microarrays) and mRNA expression level (determined using both cDNA and Affymetrix oligonucleotide microarrays). The analysis identified an association of ERBB2 overexpression with 3p copy number, a finding supported by data from human tumors and a mouse model of ERBB2-induced carcinogenesis. When we examined the correlation between DNA copy number for all 353 unique loci on the bacterial artificial chromosome microarray and drug sensitivity for 118 drugs with putatively known mechanisms of action, we found a striking negative correlation (–0.983; 95% bootstrap confidence interval, –0.999 to –0.899) between activity of the enzyme drug L-asparaginase and DNA copy number of genes near asparagine synthetase in the ovarian cancer cells. Previous analysis of drug sensitivity and mRNA expression had suggested an inverse relationship between mRNA levels of asparagine synthetase and L-asparaginase sensitivity in the NCI-60. The concordance of pharmacogenomic findings at the DNA and mRNA levels strongly suggests further study of L-asparaginase for possible treatment of a low-synthetase subset of clinical ovarian cancers. The DNA copy number database presented here will enable other investigators to explore DNA transcript-drug relationships in their own domains of research focus. [Mol Cancer Ther 2006;5(4):853–67]

Grant support: U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research Contract DE-AC03-76SF00098; NIH, National Cancer Institute grants P01 CA 64602 and P50 CA 58207 (J.W. Gray); and Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Array CGH data have been deposited in ArrayExpress (accession no. E-TABM-65).

K.J. Bussey and K. Chin contributed equally to this work.

The current address for S. Lababidi is U.S. Food and Drug Administration, Rockville, MD.

The current address for Ajay is Celera Genomics, Rockville, MD.

¹⁰ Data from these studies can be found online (http://discover.nci.nih.gov).

¹¹ http://cc.ucsf.edu/gray/public

¹² http://www.dtp.nci.nih.gov

¹³ Ajay et al., unpublished.

¹⁴ http://discover.nci.nih.gov/matchminer

¹⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org) or at the Genomics and Bioinformatics Group web site (http://discover.nci.nih.gov/host/2005_bussey_supplement/Bussey_et_al_Supplementary_information.jsp).

¹⁶ http://www.r-project.org

¹⁷ http://discover.nci.nih.gov

Received 5/16/05; revised 12/ 6/05; accepted 1/25/06.