Comparative Genomic Hybridization In Cancer Cytogenetics

Genetic alterations associated with neoplasia have been well defined in hematological malignancies by both classical and molecular cytogenetics.1-5'6-1 In contrast, there is significantly less information known about the cytogenetics and molecular cytogenetics of solid tumors. This is because of technical difficulties in the production of metaphase spreads from these tumor cells. Karyotype analysis requires viable, proliferating cells that can be arrested in the metaphase stage of the cell cycle. Cytogenetic analysis of these tumors is often hampered as many solid tumor cells fail to proliferate in vitro. For those tumors that do divide and produce metaphase spreads, the quality of the metaphase spreads is often inadequate to allow for recognition of banding patterns. There is also the question of the significance of the cytogenetic data derived from in vitro tumor cell culture as small subclones in vivo may take advantage of the in vitro conditions and thus the nonproliferating cells that constitute the main clone in vivo may escape detection by conventional cytogenetic analysis.[7] In addition, many aberrant chromosomal regions may not be identified because of the highly complex karyotypes of cultured cancer cells carrying both multiple numerical and structural chromosomal abnormalities.

Comparative genomic hybridization allows for direct analysis of genomic DNA obtained from tumor specimens, thus overcoming the problems associated with cell culturing and poor metaphase spread quality. Also, as detection of chromosomal imbalances by CGH is dependent on the aberrations being present in 30-50% or more of cells from which the DNA is extracted,1-2-1 the results derived using this technique reflect changes that are genuinely present in the majority of tumor cells. Comparative genomic hybridization analysis is limited by its inability to provide information about balanced rearrangements, the origins of structural anomalies, or the ploidy status of the cells. However, identification of specific regions of imbalance may be sufficient to provide a location for candidate genes (oncogenes and tumor suppressor genes) causative of the initiation and progression of these tumors.

The use of CGH in cancer genetics has revealed a number of novel recurring chromosomal gains, amplifications, losses, and deletion sites that escaped detection using traditional cytogenetic analysis in various tumors, including prostate cancer, testicular germ cell tumors, breast cancer, uveal melanomas, small-cell lung carcinoma, gliomas, sarcomas, head, neck, and pancreatic carcinomas, and uterine leiomyomata. The chromosomal aberrations detected by CGH have also provided prognostic information in a number of neoplasms including renal cell carcinomas, bladder cancer, cervical carcinomas, node-negative breast cancer, uveal melanoma, cutaneous melanoma, and prostate cancer. Various international CGH databases have been established including Tokyo Medical and Dental University CGH database (http:// www.cghtmd.jp/cghdatabase/index_e.html), the database of Humboldt-University of Berlin (http://amba.charite.de/ ^ksch/cghdatabase/index.htm), the Progenetix cytogenetic online database (http://www.progenetix.net), and the National Cancer Institute and National Center for Biotechnology Information Spectral Karyotyping SKY and Comparative Genomic Hybridization CGH Database (2001), (http://www.ncbi.nlm.nih.gov/sky). These databases provide a wealth of information on the CGH studies that have been done since 1992.

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