) Genetic and cytogenetic studies involving large panels of tumor cases have identified a set of chromosomal deletions that are recurrent in multiple tumor types, suggesting that they may involve tumor suppressor genes of general relevance in tumorigenesis. The goal of this research program is to identify the tumor suppressor genes that are altered in two of these chromosomal alterations and to elucidate their role in tumorigenesis: Project 1 will identify the gene involved in chromosome 6q27 deletions that are associated with non-Hodgkin's lymphoma, breast and ovarian carcinoma, renal carcinoma and, possibly, melanoma. Project 2 will elucidate the normal function and role in tumorigenesis of PTEN, the recently identified gene coding for a tyrosine phosphatase and involved in chromosome 10q23 deletions associated with breast cancer, including both sporadic and familial cases, glioblastoma, prostate cancer, endometrial cancer, and non-Hodgkin's lymphoma. Project 3 will focus on mouse models in which alterations of the familial breast cancer genes BRCA-1 and BRCA-2 will be studied for their effects on development and tumorigenesis, either alone or in combination with other genetic and epigenetic alterations involved in tumor progression. These studies will be supported by an Administrative Core. The long term goal of this Program Project is to exploit the identified genetic alterations for a better understanding of the pathogenesis of cancer. In addition, the genetic lesions identified in this project should prove useful clinically as markers for improved diagnosis and, eventually as targets for rational therapeutic intervention.
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