A critical goal in prostate cancer (PC) epidemiology is identifying the
biological mechanism underlying the progression from clinically non-
significant PC to clinically relevant PC. We propose to conduct a case-
case study comparing a group of 100 men with non-significant PC and an
age- and ethnic-matched group of 300 men with clinically relevant PC.
These two groups will be characterized by comprehensive epidemiologic
profiles and by comparison of multiple genetic alterations in their PC
lesions. The objective is to identify environmental and genetic
determinants of PC progression. The long term goal is to identify and
clone a tumor suppressor gene (rSG), frequently inactivated in PC, that
might be a future target for therapy. The hypothesis being tested is that
foci of preneoplasia or low grade cancer have experienced some, but not
all, the necessary steps to progress to invasive cancer, and that
environmental and genetic factors play a role in this progression.
The epidemiologic component will compare risk profiles of men with
respect to previously reported and putative risk factors (including
dietary intake of total fat, fatty acids, and micronutrients,
sociodemographic factors, patterns of body fat distribution, vasectomy,
family history and male patterns of balding). The working hypotheses are
that environmental factors play a role in the development of the
The molecular genetic component will focus on analysis of allele loss in
the two groups of men by screening all available paired specimens of PC
and normal tissues and/or preneoplastic lesions such as prostatic
intraepithelial neoplasia. The working hypothesis is that frequent LOH
at specific chromosomal regions,which is associated with inactivation of
tumor suppressor genes, is a major mechanism in the progression of PC and
that non-significant PC can be distinguished from clinical PC on the
basis of genetic changes. Our goal is to identify new molecular genetic
markers, highly associated with the progression of PC, and that can be
used as diagnostic and prognostic markers. In addition, this component
will focus on limiting chromosomal regions which show frequent
LOH/deletions to a specific chromosomal band or sub-bands by generating
new polymorphic microsatellite probes from microdissected chromosomal
The presence of lesions of unknown malignant potential poses a serious
therapeutic dilemma. Environmental factors in concert with genetic
alterations such as frequent LOH at specific chromosomal regions may be
important mechanisms in the progression of PC and may be of predictive
and therapeutic value.
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