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[Cancer Research 62, 6240-6245, November 1, 2002]
© 2002 American Association for Cancer Research

Molecular Biology and Genetics

Impact of DNA Amplification on Gene Expression Patterns in Breast Cancer1 ,,2

Elizabeth Hyman3, Päivikki Kauraniemi3, Sampsa Hautaniemi, Maija Wolf, Spyro Mousses, Ester Rozenblum, Markus Ringnér, Guido Sauter, Outi Monni, Abdel Elkahloun, Olli-P. Kallioniemi and Anne Kallioniemi4

Howard Hughes Medical Institute-NIH Research Scholar, Bethesda, Maryland 20892 [E. H.]; Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [E. H., P. K., S. H., M. W., S. M., E. R., M. R., A. E., O. K., A. K.]; Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33520 Tampere, Finland [P. K., A. K.]; Signal Processing Laboratory, Tampere University of Technology, FIN-33101 Tampere, Finland [S. H.]; Institute of Pathology, University of Basel, CH-4003 Basel, Switzerland [G. S.]; and Biomedicum Biochip Center, Helsinki University Hospital, Biomedicum Helsinki, FIN-00014 Helsinki, Finland [O. M.]

Genetic changes underlie tumor progression and may lead to cancer-specific expression of critical genes. Over 1100 publications have described the use of comparative genomic hybridization (CGH) to analyze the pattern of copy number alterations in cancer, but very few of the genes affected are known. Here, we performed high-resolution CGH analysis on cDNA microarrays in breast cancer and directly compared copy number and mRNA expression levels of 13,824 genes to quantitate the impact of genomic changes on gene expression. We identified and mapped the boundaries of 24 independent amplicons, ranging in size from 0.2 to 12 Mb. Throughout the genome, both high- and low-level copy number changes had a substantial impact on gene expression, with 44% of the highly amplified genes showing overexpression and 10.5% of the highly overexpressed genes being amplified. Statistical analysis with random permutation tests identified 270 genes whose expression levels across 14 samples were systematically attributable to gene amplification. These included most previously described amplified genes in breast cancer and many novel targets for genomic alterations, including the HOXB7 gene, the presence of which in a novel amplicon at 17q21.3 was validated in 10.2% of primary breast cancers and associated with poor patient prognosis. In conclusion, CGH on cDNA microarrays revealed hundreds of novel genes whose overexpression is attributable to gene amplification. These genes may provide insights to the clonal evolution and progression of breast cancer and highlight promising therapeutic targets.




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