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Grant Details

Grant Number: 5R01CA068584-04 Interpret this number
Primary Investigator: Sakr, Wael
Organization: Wayne State University
Project Title: Premalignant Lesions of the Prostate-Age and Race Study
Fiscal Year: 1998


Prostatic carcinoma (PCa) is the most commonly diagnosed malignancy in American males and is responsible for 13% of all male cancer-related deaths. African-American (AA) males have a 50% higher incidence and suffer twice the mortality rates due to this cancer compared to Caucasians (C). The reason(s) for this difference are not known. PCa can be viewed as encompassing two major forms. Latent cancers, defined as those found incidently in men without clinical evidence of having PCa, are extremely prevalent, can be identified as early as the third decade of life and show no documented racial difference in prevalence. Clinical cancers, defined as those which have come to clinical attention, are significantly less common than latent PCa, show variable rates of progression and are associated with geographic, ethnic and racial differences in incidence and mortality. Precursors of PCa are poorly defined. A morphologically well characterized entity termed high grade prostatic intraepithelial neoplasia (HGPIN) has shown strong epidemiologic association with the clinically diagnosed form of PCa. Our data has shown HGPIN to be more prevalent in AA than C males between 30 and 70+ years of age. Furthermore, extensive HGPIN diffusely involving the gland is more common in AA than C males of the same ages with extensive HGPIN appearing about a decade earlier in AA than C males. We have also observed a lack of anatomic association between HGPIN and the majority (67%) of latent PCa in young men (under age 5)) of both races. The significantly higher incidence of clinical PCa in AA men with similar prevalence of latent PCa indicates that some other factor(s) are responsible for this clinical discrepancy. Two possible explanations are that (1) HGPIN is more common and extensive in AA males and is genetically unstable as compared to C men, and 2) that a higher proportion of latent PCa anatomically related to HGPIN in AA men may be more likely to progress to a clinically manifest disease. These hypotheses will be tested using conventional whole mount histopathology performed on step-sectioned entire prostate glands. That HGPIN is more extensive in AA compared to C males in the age group of 50- 65 years, the time span preceding clinically diagnosed PCa will be confirmed. The more extensive HGPIN in AA will be evaluated for greater genetic instability by studying the frequency of loss of a tumor suppressor gene located on the short arm of chromosome 8 (8p22). The loss of this locus has been documented to be a frequent event in prostatic carcinogenesis. Biological markers of tumor aggressiveness such as larger volume, less differentiated histology, aneuploid tumor DNA content and higher rates of proliferation and angiogenic activity will also be studied. It is expected that the valuation of these parameters in AA and C men will provide strong support for the hypothesis presented and will lead to a greater understanding of the observed epidemiological differences in PCa between races.



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