TbR-I (transforming growth factor beta receptor type I) is a central determinant of the TGF-b signaling pathway. Genetic alterations of TbR-I are significantly high in our recent studies of ovarian cancer. We hypothesize that diminishing of TGF-b signaling by harboring a germline deleted allele (del(GGC)3) or somatic mutations in the TbR-I gene is associated with ovarian tumor progression. Cancers of different organs may have different propensities to accumulate genetic alterations of TbR-I. Understanding of the genetic mutation profile of TbR-I in ovarian carcinoma will help to decipher the molecular mechanisms of loss of TGF-b mediated growth inhibition. These results may provide basis for a complex epidemiologic investigation and translate into clinical applications such as diagnostic and prognostic indicators for patients. In order to better understand the etiologic relevance of genetic alterations of TbR-I in the clinical and histopathological stages of human ovarian cancer, the applicant proposes the following Specific Aims: l)to identify the ovarian cancer patients with germline deletion in TbR-I gene; 2)to determine the frequency of germline deletion in non-cancer control population; 3)to determine somatic mutations in ovarian cancer including associated metastases. These studies of the TbR-I gene will be performed on paraffin-embedded tissue sections of ovarian carcinomas and non-tumor specimens. With careful tissue microdissection and sensitive PCR-SSCP technique of analyzing a significant number of tumors at various stages and non-tumor specimens, we will obtain clues: 1 )whether frequent germline deletion (del(GGC)3) of TbR-I is a useful marker to indicate high risk of ovarian cancer development and worse prognosis; 2)whether the inactivation of TbR-I gene plays an important role in the switch from non-invasive to invasive and metastatic cancer. The information obtained in this project will provide a basis for the evaluation of the genetic changes as possible indicators that distinguish patients with highest risk of developing advanced disease. These studies may eventually lead to better strategies for cancer prevention and intervention.
