192
Cancer of the Prostate: Molecular Genetics
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Adenocarcinoma of the prostate is one of the most common cancers in men
worldwide and is the second leading cause of cancer-speciFc death in the United
States. Over the past 15 years, signiFcant advances have been made in the treatment
of prostate cancer, largely owing to earlier diagnosis and the evolution of surgical
techniques and improvements in radiation therapy. Nevertheless, tremendous
uncertainty and controversy exist regarding the appropriate clinical management
of prostate cancer in many cases. Similarly, despite the magnitude of the problem,
understanding of the pathogenesis, biology, and natural history of human prostate
cancer remains incomplete and unclear. Progress has been made in the past
decade in elucidating the molecular and genetic changes involved in prostate cancer
development and progression. A better understanding of the underlying disease
mechanisms will allow rational treatment strategies and improved outcomes. The
classic model of tumor development describes a multistep process in which a
series of genetic alterations leads to aberrant, uncontrolled cell growth. This is
best characterized in the case of colon cancer, for which speciFc genetic changes
have been correlated with clinical and pathologic disease progression. These genetic
alterations can be both hereditary (germ-line mutation) and acquired (somatic
mutation). The paradigm is less established in prostate cancer (±ig. 1). We discuss
the current understanding of the molecular genetics and biology of prostate cancer
development, including genetic predispositions, early changes associated with
prostatic intraepithelial neoplasia (PIN), and the traditional classes of genes involved
in promoting and repressing cancer development (protooncogenes/oncogenes and
tumor suppressor genes, respectively). In addition, we describe recent studies on
the role of genetic instability, telomerases, growth factors, cell-adhesion molecules,
DNA ethylation, and the androgen receptor (AR) in prostate cancer.
1
Hereditary Factors
Multiple etiologies have been proposed to
contribute to the development of prostate
cancer. Environmental factors are likely
play a major role in most cases; however,
inherited genetic factors are clearly impor-
tant in some men. Epidemiologic analysis
of almost 3000 men in the Utah Cancer
Registry demonstrated familial clustering
of prostate cancer patients, even greater
than that for both breast and colon can-
cer, for which a hereditary component has
already been demonstrated. The risks of
developing the disease are dependent on
both the number of affected Frst-degree
relatives, and early age of disease on-
set. Using segregation analysis in 691
families, a model of a rare autosomal
dominant susceptibility gene with an al-
lele frequency of 0.006 and penetrance
of 89% at 85 years of age was proposed.
Overall, this gene may account for approx-
imately 9% of all prostate cancer cases but
an increased proportion in those patients
diagnosed at earlier ages. The criteria for
hereditary prostate cancer include a clus-
ter of at least three Frst-degree relatives
with disease, at least two relatives with
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