Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer

The biological significance of DNA amplification in cancer is thought to be due to the selection of increased expression of a single or few important genes. However, systematic surveys of the copy number and expression of all genes within an amplified region of the genome have not been performed. He re we have used a combination of molecular, genomic, and microarray technol ogies to identify target genes for 17q23, a common region of amplification in breast cancers with poor prognosis. Construction of a 4-Mb genomic conti g made it possible to define two common regions of amplification in breast cancer cell lines. Analysis of 184 primary breast tumors by fluorescence in situ hybridization on tissue microarrays validated these results with the highest amplification frequency (12.5%) observed for the distal region. Bas ed on GeneMap'99 information, 17 known genes and 26 expressed sequence tags were localized to the contig. Analysis of genomic sequence identified 77 a dditional transcripts. A comprehensive analysis of expression levels of the se transcripts in six breast cancer cell lines was carried out by using com plementary DNA microarrays. The expression patterns varied from one cell li ne to another, and several overexpressed genes were identified. Of these, R PS6KB1, MUL, APPBP2, and TRAP240 as well as one uncharacterized expressed s equence tag were located in the two common amplified regions. In summary, c omprehensive analysis of the 17q23 amplicon revealed a limited number of hi ghly expressed genes that may contribute to the more aggressive clinical co urse observed in breast cancer patients with 17q23-amplified tumors.