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 addition, it has been possible to determine the complex structure of homogeneously staining regions in several cases establishing that these structures are frequently composed of DNA segments derived from multiple chromosomes and intermingled to form an abnormal region. In order to isolate candidate target genes from these regions, we have developed technologies based on chromosome microdissection, and integrated genome mapping, including cDNA microarray analysis. These technologies been 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. For example, in breast cancer, candidate genes can function as coactivators of the estrogen receptor. These genes will be utilized to determine the clinical significance of gene amplification in various malignancies. In addition, their mechanism of action will be studied with model systems based on gene transfer, gene inactivation, and biochemical techniques. This is a powerful approach for the identification of genes playing a causal role in disease genesis or progression.