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.