Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel.
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.
Bussey
Kimberly J
KJ
Laboratory of Molecular Pharmacology, National Cancer Institute, Building 37, Room 5056, NIH, MSC 4255, 9000 Rockville Pike, Bethesda, MD 20892-4255, USA.
Chin
Koei
K
Lababidi
Samir
S
Reimers
Mark
M
Reinhold
William C
WC
Kuo
Wen-Lin
WL
Gwadry
Fuad
F
Ajay
Kouros-Mehr
Hosein
H
Fridlyand
Jane
J
Jain
Ajay
A
Collins
Colin
C
Nishizuka
Satoshi
S
Tonon
Giovanni
G
Roschke
Anna
A
Gehlhaus
Kristen
K
Kirsch
Ilan
I
Scudiero
Dominic A
DA
Gray
Joe W
JW
Weinstein
John N
JN
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007621:Karyotyping; D009363:Neoplasm Proteins / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*; D012334:RNA, Neoplasm / Q000187:drug effects* / Q000235:genetics
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm