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. 2001 May 8;98(10):5711-6.
doi: 10.1073/pnas.091582298. Epub 2001 May 1.

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

O Monni  1 , M Barlund, S Mousses, J Kononen, G Sauter, M Heiskanen, P Paavola, K Avela, Y Chen, M L Bittner, A Kallioniemi
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Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer

"V体育官网" O Monni et al. Proc Natl Acad Sci U S A. .

Abstract

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. Here we have used a combination of molecular, genomic, and microarray technologies to identify target genes for 17q23, a common region of amplification in breast cancers with poor prognosis. Construction of a 4-Mb genomic contig 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. Based on GeneMap'99 information, 17 known genes and 26 expressed sequence tags were localized to the contig. Analysis of genomic sequence identified 77 additional transcripts. A comprehensive analysis of expression levels of these transcripts in six breast cancer cell lines was carried out by using complementary DNA microarrays. The expression patterns varied from one cell line to another, and several overexpressed genes were identified. Of these, RPS6KB1, MUL, APPBP2, and TRAP240 as well as one uncharacterized expressed sequence tag were located in the two common amplified regions. In summary, comprehensive analysis of the 17q23 amplicon revealed a limited number of highly expressed genes that may contribute to the more aggressive clinical course observed in breast cancer patients with 17q23-amplified tumors. VSports手机版.

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Figures

Figure 1
Figure 1
(A) Physical and transcript map of the 17q23 region. A minimal tiling path consisting of 57 clones between markers WI-16256 and D17S948 is shown. YAC clones are symbolized by thick bars and BAC, P1 artificial chromogene (PAC), and P1 clones by thin bars. A gap of unknown size in the contig is marked with an arrow. STSs are indicated on the top of the contig while ESTs and known genes (marked in red) are shown under the contig. The clones marked with red bars were used for copy number analysis as illustrated in B. The map is not drawn in scale. (B) Amplicon mapping in MCF7 and BT-474 breast cancer cell lines. DNA sequence copy number changes were analyzed by interphase FISH using 22 clones from the contig (indicated in red in A). The mean absolute copy number per cell is plotted for each probe.
Figure 2
Figure 2
Amplicon mapping in primary breast tumors by FISH to tissue microarray. (A) Amplification frequencies of 10 clones from the 17q23 contig in 184 primary breast tumors. (B) Amplification patterns in 27 primary breast tumors that showed amplification with at least one of the probes tested. Rows correspond to individual tumor samples and columns to each clone. Empty boxes represent no copy number increase and shaded boxes indicate amplification.
Figure 3
Figure 3
Copy number (A) and expression (B) survey of chromosome 17-specific genes in MCF7 breast cancer cell line by cDNA microarrays. The copy number and expression ratio data are plotted as a function of the position of the clones in the radiation hybrid map in cR scale. Individual data points are connected with a line. A moving average of three (a mean copy number ratio of three adjacent clones) is shown in A. (C) The copy number ratio as a function of the expression ratio in MCF7 breast cancer cell line. The oval indicates a set of genes that are both highly amplified and overexpressed. Each clone was printed in duplicate on the array, and results from both observations are shown.
Figure 4
Figure 4
Expression map of the 17q23 region in six breast cancer cell lines. Each column represents one breast cancer cell line and each row a transcribed sequence arranged according to their physical order in the 17q23 contig from centromere to telomere. ESTs obtained from the genomic sequence are shown only if they were overexpressed in at least three cell lines and are indicated with an *. Color coding for the expression ratio is shown below the expression map. The locations of the common amplification regions identified in the breast cancer cell lines are indicated with red vertical bars.
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