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

Kimberly J. Bussey, Kwang-Yung Chin, Samir Lababidi, Mark Reimers, William C. Reinhold, Wen Lin Kuo, Fuad Gwadry, Ajay, Hosein Kouros-Mehr, Jane Fridlyand, Ajay Jain, Colin Collins, Satoshi Nishizuka, Giovanni Tonon, Anna Roschke, Kristen Gehlhaus, Ilan Kirsch, Dominic A. Scudiero, Joe Gray, John N. Weinstein

Research output: Contribution to journalArticle

124 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)853-867
Number of pages15
JournalMolecular Cancer Therapeutics
Volume5
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

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Gene Expression
Cell Line
DNA
Asparaginase
Pharmaceutical Preparations
Aspartate-Ammonia Ligase
Messenger RNA
Bacterial Artificial Chromosomes
Ovarian Neoplasms
Neoplasms
Carcinogenesis
Comparative Genomic Hybridization
Gene Dosage
Neoplasm Genes
Pharmacogenetics
Ligases
Oligonucleotide Array Sequence Analysis
Complementary DNA
Chromosomes
Research Personnel

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel. / Bussey, Kimberly J.; Chin, Kwang-Yung; Lababidi, Samir; Reimers, Mark; Reinhold, William C.; Kuo, Wen Lin; Gwadry, Fuad; Ajay; Kouros-Mehr, Hosein; Fridlyand, Jane; Jain, Ajay; Collins, Colin; Nishizuka, Satoshi; Tonon, Giovanni; Roschke, Anna; Gehlhaus, Kristen; Kirsch, Ilan; Scudiero, Dominic A.; Gray, Joe; Weinstein, John N.

In: Molecular Cancer Therapeutics, Vol. 5, No. 4, 04.2006, p. 853-867.

Research output: Contribution to journalArticle

Bussey, KJ, Chin, K-Y, Lababidi, S, Reimers, M, Reinhold, WC, Kuo, WL, Gwadry, F, Ajay, Kouros-Mehr, H, Fridlyand, J, Jain, A, Collins, C, Nishizuka, S, Tonon, G, Roschke, A, Gehlhaus, K, Kirsch, I, Scudiero, DA, Gray, J & Weinstein, JN 2006, 'Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel', Molecular Cancer Therapeutics, vol. 5, no. 4, pp. 853-867. https://doi.org/10.1158/1535-7163.MCT-05-0155
Bussey, Kimberly J. ; Chin, Kwang-Yung ; Lababidi, Samir ; Reimers, Mark ; Reinhold, William C. ; Kuo, Wen Lin ; Gwadry, Fuad ; Ajay ; Kouros-Mehr, Hosein ; Fridlyand, Jane ; Jain, Ajay ; Collins, Colin ; Nishizuka, Satoshi ; Tonon, Giovanni ; Roschke, Anna ; Gehlhaus, Kristen ; Kirsch, Ilan ; Scudiero, Dominic A. ; Gray, Joe ; Weinstein, John N. / Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 4. pp. 853-867.
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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.",
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AU - Reimers, Mark

AU - Reinhold, William C.

AU - Kuo, Wen Lin

AU - Gwadry, Fuad

AU - Ajay,

AU - Kouros-Mehr, Hosein

AU - Fridlyand, Jane

AU - Jain, Ajay

AU - Collins, Colin

AU - Nishizuka, Satoshi

AU - Tonon, Giovanni

AU - Roschke, Anna

AU - Gehlhaus, Kristen

AU - Kirsch, Ilan

AU - Scudiero, Dominic A.

AU - Gray, Joe

AU - Weinstein, John N.

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