MOLECULAR CYTOGENETICS OF GENE AMPLIFICATION

Human Genome Research

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Abstract

Using DNA probes generated by chromosome microdissection, cDNA microarray analysis, and CGH findings, we have identified a series of chromosomal regions involved in human breast, ovarian and prostate cancer. In order to isolate candidate target genes from these regions, we have developed technologies based on chromosome microdissection, and integrated genome mapping, including DNA microarray analysis. These technologies are being utilized to isolate candidate genes from amplified regions in breast cancer, ovarian cancer, and sarcomas. The methodology previously described illustrates the importance of developing rapid techniques for the identification of genes amplified in a series of key human tumors. In addition to recognizing known sites of gene amplification, we have identified several previously unidentified genes amplified in breast, prostate and ovarian cancers. We are currently focusing on breast cancer where candidate genes can function as coactivators of the estrogen receptor. Their mechanism of action will be studied with model systems based on gene transfer, gene inactivation, and biochemical techniques. In addition, we are developing a comprehensive database of amplified chromosomal regions in soft tissue and bone sarcomas using microarray based CGH. This is a powerful approach for the identification of genes playing a causal role in disease genesis or progression and may provide novel prognostic markers as well as therapeutic targets.