IDENTIFICATION OF A 12P PROSTATE TUMOR SUPPRESSOR GENE

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DESCRIPTION (Applicant's Description): The two objectives of this application are to support my training as a physician scientist and to identify novel tumor suppressor gene(s) with functional significance in prostate carcinoma. This award will facilitate my transition to independent investigator by providing detailed molecular laboratory training under the mentorship of Dr. Paul Goodfellow, the Director of the Cancer Genetics Research Program at the School of Medicine. Dr. Goodfellow is ideally suited to be my mentor because his research into the genetic determinants of endometrial tumorigenesis closely parallels the research proposed in this application; therefore, all techniques described in this application have been used in his laboratory. Importantly, he has previously successfully mentored several physician scientists. A didactic program in molecular biology will complement the intellectual environment provided by Dr. Goodfellow's lab, the Cancer Genetics Research Program, and the Division of Urology. I have recently reported the discovery of a 1-2Mb homozygous deletion (HZD) at 1 2 p12-13 in metastatic prostate cancer specimens. Frequent loss of heterozygosity (LOH) of the same region is frequently seen in tumors. The smallest common region of LOH encompasses the location of the HZD and narrows the consensus deletion region to approximately 600kb. The frequency and regional specificity of these deletions (LOH and HZD) point to a prostate cancer suppressor gene at this site. The experimental rationale and methods proposed to clone this 12pl2-13 prostate tumor suppressor gene are as follows: (I) Define the minimal candidate region at 12pl2-13. An overlapping HZD in a second prostate cancer specimen would narrow the region of interest. I will use computational and laboratory screening techniques to identify candidate genes in this region and then determine if candidates are HZD in a panel of prostatic tumors. (II) Investigate candidate genes inactivating genetic events. If these genes contribute to prostate tumorigenesis, inactivating genetic events will be present in the remaining prostate carcinoma specimens. Cancer specimens will be interrogated for mutations and promotor methylation. (III) Functional demonstration of tumor suppression. If loss of function of the 12p12-13 gene contributes to tumor formation, reintroduction of the wild- t y p e , but not mutant cDNA into prostate cell lines will suppress tumorigenesis. The identification of a novel tumor suppressor would provide a target for better prostate cancer therapy and/or more accurate prognostic information for men newly diagnosed with the disease.