Distortion of the cell genome characterizes neoplastic transformation. Genetic alterations that occur in tumor cells lead to activation of positive regulators of cell growth or survival and inactivation of factors that suppress these processes. A particular type of genomic alteration, chromosomal segment copy number imbalance, plays a significant role in malignant transformation: chromosomal deletions may inactivate tumor suppressor genes, while chromosomal segment amplifications may increase the gene dosage of oncogenes. In this study, we propose to apply a new technique, Comparative Hybridization of AP-PCR Arrays (CHAPA), which was developed in our laboratory, for high resolution profiling of breast tumors for DNA copy number alterations. This will allow the detection of single DNA copy number losses or gains at thousands of sites throughout the genome of the cancer cells (Specific Aim 1). We hypothesize that such genetic signatures may embrace the information on what cancer genes were responsible for the development and progression of each tumor and, consequently, the resulting pathologic behavior of tumor cells and their responsiveness to treatment. This general hypothesis will be tested by the analysis of genetic profiles to differentiate breast tumors according to their pathways of tumorigenesis (known or novel) and by the analysis of genetic profiles of breast tumors in association with their clinicopathologic characteristics, recurrence, and patient's survival to reveal genetic markers for cancer diagnosis and prognosis. Once frequent (common for independent tumors) genomic alterations have been identified, they will be compared with the loci known to play a role in breast cancer development. The genetic aberrations in chromosomal regions that do not contain known cancer genes will be selected for further characterization with the ultimate goal to identify the underlying novel cancer genes (Specific Aim 3). These experiments will provide a comprehensive view on the role of genetic aberrations in breast tumorigenesis. They will also help to identify genetic markers for breast cancer diagnosis, development, and prognosis and facilitate the identification, mapping, and eventual isolation of novel cancer genes. ? ?
