Functional genomics of cancer

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One of the major problems in cancer biology is to define the aberrant pattern of gene expression in tumor cells and to relate this pattern to specific genomic alterations which occur during tumorigenesis. To address this issue, a novel technology, DNA microarray hybridization is being applied to analyze the consequences of chromosome anomalies at the level of gene expression. Using a robotic device, it is possible to print thousands of DNA probes representing the complete genome on a single microscope slide. Fluorescent probes prepared from any cell or tissue source of interest are then hybridized to these arrays providing a large scale view of gene expression. The ultimate goal of this project is genome wide expression analysis. In this fashion, it is proving possible to profile individual diseases, and to determine the consequences of a given genetic alteration on gene expression. This technology is now being applied in model systems carrying alterations in tumor specific genes affected by translocation, activation mutation, amplification or deletion, and in models which have distinct biological properties such as metastasis or responsiveness to hormones. Information obtained from model systems is then integrated with gene expression profiles derived from the statistical analysis of expression data from tissue specimens. Our recent efforts have applied this technology to pediatric cancers, adult sarcomas, melanoma and breast cancers. We have been able to establish the potential of microarrays for the accurate diagnosis of pediatric cancers and for distinguishing estrogen receptor positive breast cancers from receptor negative tumors. Using data from laboratory models we have uncovered patterns of gene expressionrelated to important clinical properties of cancers such as estrogen sensitivity in breast cancer and metastasis in melanoma and osteosarcoma.