Cytogenetic and molecular biological studies have demonstrated deletion of one or more sequence domains that map to the short arm of chromosome 8 (8p) in tumors from several organ systems, including human prostate tumors. Recent studies in our laboratory utilizing interphase fluorescence in situ hybridization (FISH) analysis of prostate tissue sections with unique sequence and pericentromeric probes demonstrate high (>70%) frequencies of 8p22 sequence losses in prostate tissue, sometimes accompanied by gain or loss of other chromosome 8 sequences. Based upon these observations, we hypothesize that: 1) """"""""simple"""""""" allelic loss of 8p sequences (e.g., deletion of specific 8p sequences alone without alterations of chromosome 8 dosage) is an important event in prostate tumorigenesis, but that 2) the process of prostate tumorigenesis may be further promoted by a) concurrent or subsequent changes in the dosage (gain or loss) of other linked chromosome 8 loci, and b) a widespread rather than focal pattern of 8p allelic loss and/or chromosome 8 dosage alterations in the tumor. If this hypothesis is true, we would expect our studies to show that, within tumors with 8p loss that share """"""""identical"""""""" clinicopathological characteristics, there exists a subset of tumors with widespread (rather than focal) 8p allelic loss and/or alterations in chromosome 8 dosage that are more likely to recur with worse prognosis after radical prostatectomy. Therefore, the goals of this project are to utilize FISH techniques to determine the frequency and pattern of 8p sequence deletions and chromosome 8 dosage alterations as part of a genetic model of prostate tumorigenesis, and to ascertain which of these factors might serve as indicators of worse prognosis. To accomplish these goals, we have organized the research into three specific aims:
SPECIFIC AIM 1 : Define and compare the frequency of 8p sequence losses and chromosome 8 dosage alterations in: a) normal and hyperplastic (BPH) prostatic epithelium; b) prostatic intraepithelial neoplasias (PINs); c) malignant lesions from """"""""less advanced"""""""" cancers (Gleason score 4-6 and localized disease) and those from """"""""more advanced"""""""" cancers (Gleason score 7-9 and invasive disease);
SPECIFIC AIM 2 : Define the type and pattern of 8p sequence losses or changes in chromosome 8 dosage (widespread or focal) in tissues by enumerating probe signal within discrete microscopic coordinates;
SPECIFIC AIM 3 : Determine whether the frequency, type, pattern or dosage of 8p sequence losses and chromosome 8 dosage alterations may serve as useful prognostic indicators by determining whether they predict tumor recurrence, using serum PSA and other clinical parameters as indicators of recurrence. The information obtained in pursuit of these goals should be useful towards defining the roles of 8p sequence losses and chromosome 8 dosage in one or more potential neoplastic pathways in the prostate, and in defining the potential prognostic significance of these events.
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