Introduction

Prostate Anatomy & Function

The prostate is a small gland, about the size and shape of a quail's egg. Nestled in the man's
pubic bone and surrounded by the pelvic muscles, the prostate gland will respond to pressure
applied through the rectum.

The main function of the prostate is reproduction. The testicles produce sperm, the "little
guys" that fertilize eggs. The vas deferens carries this sperm to the prostate, where it mixes
with fluid from the prostate and seminal vesicles. When you have an orgasm, you ejaculate
this fluid, which is comprised of 5% sperm and 95% seminal/prostate fluid.

Prostate Problems
The prostate can play host to a few common problems: Benign Prostatic Hyperplasia (BPH) is
characterized by a non-cancerous growth of the prostate, and Prostatitis is an inflammation of
the prostate. Both conditions are relatively easy to treat. Prostate cancer, however, is far more
serious: currently, it is the leading cancer diagnosed among men in the United States.

Although we know very little about what causes prostate cancer, the medical community has
discovered much about how to diagnose it. The prostate produces a substance known as the
Prostate Specific Antigen (PSA), a small amount of which continuously leaks into the
bloodstream. High levels of PSA can be associated with prostate cancer. Doctors can easily
test the level of PSA in your blood. However, some problems can only be diagnosed with a
rectal exam, which is why you need a PSA blood test AND a rectal exam annually. While
these exams are not foolproof, there is evidence that early detection can be helpful in
preventing the spread of cancer.

What is prostate cancer?

Prostate cancer is a malignant (cancerous) tumor (growth) that consists of cells from the
prostate gland. The tumor usually grows slowly and remains confined to the gland for many
years. During this time, the tumor produces little or no symptoms or outward signs
(abnormalities on physical examination). As the cancer advances, however, it can spread
beyond the prostate into the surrounding tissues (local spread). Moreover, the cancer also
can metastasize (spread even farther) throughout other areas of the body, such as the bones,
lungs, and liver. Symptoms and signs, therefore, are more often associated with advanced
prostate cancer.
Why is prostate cancer important?

In 1999, 185,000 new cases of prostate cancer were diagnosed in the United States. What's
more, 31,000 deaths related to prostate cancer are expected in the year 2000. Thus, prostate
cancer is the most common malignancy in American men and the second leading cause of
deaths from cancer, after lung cancer. Most experts in this field, therefore, recommend that
beginning at age 40, all men should undergo yearly screening for prostate cancer.

What causes prostate cancer?

The cause of prostate cancer is unknown, but the cancer is thought not to be related to
benign prostatic hypertrophy (BPH). The risk (predisposing) factors for prostate cancer
include advancing age, genetics (heredity), hormonal influences, and such environmental
factors as toxins, chemicals, and industrial products. The chances of developing prostate
cancer increase with age. Thus, prostate cancer under age 40 is extremely rare, while it is
common in men older than 80 years of age. As a matter of fact, some studies have suggested
that among men over 80, between 50 and 80 percent of them may have prostate cancer!

Genetics (heredity), as just mentioned, plays a role in the risk of developing a prostate cancer.
For example, black American men have a higher risk of getting prostate cancer than do
Japanese or white American men. Environment, diet, and other unknown factors, however,
can modify such genetic predispositions. For example, prostate cancer is uncommon in
Japanese men living in their native Japan. However, when these men move to the United
States, their incidence of prostate cancer rises significantly. Prostate cancer is also more
common among family members of individuals with prostate cancer. Thus, a person whose
father, grandfather, or even uncle has prostate cancer is at an increased risk for also
developing prostate cancer. To date, however, no specific prostate cancer gene has been
identified and verified. (Genes, which are situated on chromosomes within the nucleus of
cells, are the chemical compounds that determine specific traits in individuals.)

Testosterone, the male hormone, directly stimulates the growth of both normal prostate tissue
and prostate cancer cells. Not surprisingly, therefore, this hormone is thought to be involved in
the development and growth of prostate cancer. The important implication of the role of this
hormone is that decreasing the level of testosterone should be (and usually is) effective in
inhibiting the growth of prostate cancer.

Environmental factors, such as cigarette smoking and diets that are high in saturated fat,
seem to increase the risk of prostate cancer. Additional substances or toxins in the
environment or from industrial sources might also promote the development of prostate
cancer, but these have not yet been clearly identified

What are the symptoms of prostate cancer?

In the early stages, prostate cancer often causes no symptoms for many years. As a matter of
fact, these cancers frequently are first detected by an abnormality on a blood test (the PSA,
discussed below) or as a hard nodule (lump) in the prostate gland. Usually, the doctor first
feels the nodule during a routine digital (done with the finger) rectal examination. (Note in the
diagram that the prostate gland is right in front of the rectum.) As the cancer enlarges and
presses on the urethra, the flow of urine diminishes and urination becomes more difficult.
Patients may also experience burning with urination or blood in the urine. As the tumor
continues to grow, it can completely block the flow of urine, resulting in a painfully obstructed
and enlarged urinary bladder.

In the later stages, prostate cancer can spread locally into the surrounding tissue or the
nearby lymph nodes, called the pelvic nodes. The cancer then can spread even farther
(metastasize) to other areas of the body. The doctor on a rectal examination can sometimes
detect local spread into the surrounding tissues. That is, the physician can feel a hard, fixed
(not moveable) tumor extending from and beyond the gland.
 Prostate cancer usually metastasizes first to the lower spine or the pelvic bones (the bones
connecting the lower spine to the hips), thereby causing back or pelvic pain. The cancer can
then spread to the liver and lungs. Metastases (areas to which the cancer has spread) to the
liver can cause pain in the abdomen and jaundice (yellow color of the skin) in rare instances.
Metastases to the lungs can cause chest pain and coughing.

Frequency

With the advent of PSA screening, a greater number of men require education
about prostate cancer and how it is diagnosed, staged, and treated in order to
select the most appropriate treatment.

According to recent figures from the American Cancer Society, 220,900 new
cases were diagnosed in 2003 and 28,900 men will die of prostate cancer
(see Image 1). Prostate cancer is rarely diagnosed in men younger than 40
years, and it is uncommon in men younger than 50 years.

Prevalence rates of prostate cancer remain significantly higher in African

American men than in white men, while the prevalence in Hispanic men is
similar to that of non-Hispanic white men. Hispanic men and African American
men present with more advanced disease, most likely related to external (eg,
income, education, insurance status) and cultural factors. In addition, African
American men generally have higher levels of testosterone, which may
contribute to the higher incidence of carcinoma.

Between 1989 and 1992, incidence rates of prostate cancer increased

dramatically, probably because of earlier diagnoses in asymptomatic men as
a result of the increased use of serum PSA testing. In fact, the incidence of
organ-confined disease at diagnosis has increased because both PSA testing
and standard DRE are performed.

Prostate cancer incidence rates are currently declining, with peak rates in
1992 among white men and in 1993 among African American men.
During 1992-1996, mortality rates for prostate cancer declined significantly,
approximately 2.5% per year (see Image 1). Although mortality rates are
continuing to decline among white and African American men, mortality rates
in African American men remain 2.3 times as high as rates in white men
based on 2003 American Cancer Society projections.

Prostate cancer is also found during autopsies performed following other

causes of death. The rate of this latent or autopsy cancer is much greater
than that of clinical cancer. In fact, it may be as high as 80% by age 80 years.

What are the screening tests for prostate cancer?

Screening tests are those that are done at regular intervals to detect a disease such as
prostate cancer at an early stage. If the result of a screening test is normal, the disease is
presumed not to be present. If a screening test is abnormal, the disease is then suspected to
be present, and further tests usually are needed to confirm the suspicion (that is, to make the
diagnosis definitively). Prostate cancer usually is suspected initially because of an
abnormality of one or both of the two screening tests that are used to detect prostate cancer.
These screening tests are a digital rectal examination and a blood test called the prostate
specific antigen (PSA).

In the digital rectal examination, the doctor feels (palpates) the prostate gland with his index
finger in the rectum to detect abnormalities of the gland. Thus, a lump, irregularity, or
hardness felt on the surface of the gland is a finding that is suspicious for prostate cancer.
Accordingly, doctors usually recommend doing a digital rectal examination annually in men
age 40 and over.

The PSA test is a simple, reproducible, and accurate blood test. It is used to detect a protein
(the prostate specific antigen) that is released from the prostate gland into the blood. Most
importantly, the level of the PSA is usually higher in people with prostate cancer than in
people without the cancer. The PSA, therefore, is valuable as a screening test for prostate
cancer. Accordingly, doctors usually recommend doing a PSA annually in men age 50 and
over. Furthermore, for men who have high risks for prostate cancer as discussed above, most
doctors recommend starting the PSA screening at an even younger age (for example, at age
40).

Results of the PSA test under 4 nanograms per milliliter of blood are generally considered
normal. (See the next two sections on false-positive elevations of the PSA and on refinements
in the PSA test.) Results between 4 and 10 are considered borderline. These borderline
values are interpreted in the context of the patient's age, symptoms, signs, family history, and
changes in the PSA levels over time. Results higher than 10 are considered abnormal,
suggesting the possibility of prostate cancer. The higher the PSA value, the more likely the
diagnosis of prostate cancer. Moreover, the level of PSA tends to increase when the cancer
has progressed from organ-confined prostate cancer to local spread to distant (metastatic)
spread. Very high values, such as 30 or 40 and over, are usually caused by prostate cancer

Abnormal rectal examination findings

Findings from the DRE are crucial. An irregular, firm prostate or nodule is typical, but many
cancers are found in prostates that feel normal. Pay careful attention to the prostate
consistency, along with the seminal vesicles and adjacent organs, to detect spread of the
disease to these structures.

• Overdistended bladder due to outlet obstruction

• Neurologic findings secondary to cord compression: Other subtle findings, such as
paresthesias or wasting, are uncommon.
 • Lower extremity lymphedema
• Supraclavicular adenopathy
• Lower extremity deep venous thrombosis
• Cancer cachexia

Transrectal ultrasound

TRUS is used to examine the prostate for hypoechoic areas, which are commonly associated
with cancers but are not specific enough for diagnostic purposes. At least 6 or, more recently,
10 or more systematic biopsy specimens of peripheral and, occasionally, transitional zones
are taken under ultrasound guidance. Samples should include most areas of the gland,
irrespective of ultrasonographic abnormalities.

Differential diagnosis

• Benign prostatic hypertrophy

• Calculi
• Prostatic cysts
• Prostatic tuberculosis
• Prostatitis

http://www.medicinenet.com/prostate_cancer/page3.htm

How is prostate cancer diagnosed?

Prostate cancer is diagnosed from the results of a biopsy of the prostate gland. If the digital
rectal exam of the prostate or the PSA blood test is abnormal, a prostate cancer is suspected.
A biopsy of the prostate is usually then recommended. The biopsy is done from the rectum
(trans-rectally) and is guided by ultrasound images of the area. A small piece of prostate
tissue is withdrawn through a cutting needle. A pathologist then examines the tissue under a
microscope for signs of cancer in the cells of the tissue.

When prostate cancer is diagnosed on the biopsy tissue, the pathologist will then grade each
of two pieces of the tissue from 1 to 5 on the Gleason scale. The scale is based on certain
microscopic characteristics of the cancerous cells and reflects the aggressiveness of the
tumor. The two scores are then added together. Sums of 2 to 4 are considered low, indicating
a slowly growing tumor. Sums of 5 and 6 are intermediate, representing an intermediate
degree of aggressiveness. Sums of 7 to 10 are considered high, signaling a rapidly growing
tumor with the worst prognosis (outcome).

Gleason scores can be helpful in guiding treatment that is based, at least in part, on the
aggressiveness of the tumor. The principal application of the Gleason score, however, is in
predicting the risk for death from a prostate cancer. Thus, recent studies have shown that
men with Gleason scores of 2 to 4 face a minimal risk (4 to 7%) of death from prostate cancer
over the ensuing 15 years, while men with scores of 8 to 10 face a high risk (60 to 87%) of
death from prostate cancer over the 15 year period.

How is the staging of prostate cancer done?

The staging of a cancer refers to determining the extent of the disease. Once a prostate
cancer is diagnosed on a biopsy, additional tests are done to assess whether the cancer has
spread beyond the gland. For this assessment, biopsies of the surrounding organs, such as
the rectum or urinary bladder, or of the nearby (pelvic) lymph nodes might be done. In
 addition, imaging tests are usually performed. For example, radionuclide bone scans can
determine if there is a spread of the tumor to the bones. Additionally, CAT scans (coaxial
tomography) and MRIs (magnetic resonance imaging) can determine if the cancer has spread
to adjacent tissues or organs such as the bladder or rectum or to other parts of the body such
as the liver or lungs.

In brief, doctors do the staging of prostate cancer based primarily on the results of the
prostate biopsy, possibly other biopsies, and imaging tests. In staging a cancer, doctors
assign various letters and numbers to the cancer, depending on which of the classifications
for staging they use. The numbers and letters in the different classifications define the volume
or amount of the tumor and the spread of the cancer. The stage of the prostate cancer,
therefore, helps to predict the expected course of the disease and determine the choice of
treatment.

Two main systems are used to stage prostate cancer. In the American urologic staging
system, stage A describes a minimal cancer that can neither be palpated (felt) on physical
examination nor seen by imaging techniques. Such a tumor is so small that it can be detected
only by viewing it under a microscope. Stage B refers to a larger cancer that may be palpated,
but that still is confined (localized) to the prostate gland. Stage C indicates local spread
beyond the prostate into the surrounding tissues. Stage D1 signifies a spread to the nearby
(pelvic) lymph nodes and D2 is for distant spread (metastasis), for example, to the bones,
liver, or lungs.

The other main system for staging prostate cancer is called the tumor, nodes, and metastasis
(TNM) classification. In this system, T1 and T2 are equivalent to stage A and B (respectively)
in the American urologic system. T3 describes cancer that extends just beyond the capsule
(coat) of the prostate, and T4 describes cancer that is fixed to the surrounding tissues. N1 is
equivalent to Stage D1 and M1 is equivalent to D2.

What Are The Risk Factors for Prostate Cancer?

A risk factor is anything that increases your chance of developing a disease such as cancer. Different
cancers have different risk factors. For example, exposing skin to strong sunlight is a risk factor for skin
cancer. Smoking is a risk factor for cancers of the lungs, mouth, throat, larynx, bladder, and several other
organs. But having a risk factor, or even several, does not mean that you will get the disease.

Many people with one or more risk factors never develop cancer, while others with this disease may have
no known risk factors. It is important, however, that you know about risk factors so that you can try to
change any unhealthy lifestyle behaviors or can choose to have the early detection tests for a potential
cancer.

Although we don’t yet completely understand the causes of prostate cancer, researchers have found
several factors that increase the risk of developing this disease.
Age

The chance of having prostate cancer increases rapidly after age 50. About two thirds of all prostate
cancers are diagnosed in men over the age of 65. It is still unclear why this increase with age occurs.

Race

Prostate cancer occurs about 60% more often in African-American men than in white American men.
Compared with men of other races, African-American men are more likely to be diagnosed at an
advanced stage. African-American men are more than twice as likely to die of prostate cancer as white
men. Prostate cancer occurs less frequently in Asian men than in whites. Hispanic men develop prostate
cancer at similar rates as white men. The reasons for these racial differences are not clear.

http://www.medicinenet.com/prostate_cancer/page3.ht

Nationality

Prostate cancer is most common in North America and northwestern Europe. It is less common in Asia,
Africa, Central America, and South America. The reason for this is not well understood, but we know that
is not simply due to better screening in North America and Europe.
Family History

Prostate cancer seems to run in some families, suggesting an inherited or genetic factor. Having a father
or brother with prostate cancer more than doubles a man's risk of developing this disease. (The risk is
higher for men with an affected brother than for those with an affected father.) The risk is much higher for
men with several affected relatives, particularly if their relatives were young at the time of diagnosis.

Scientists have identified several inherited genes that seem to increase prostate cancer risk (see next
section), but they probably account for only a small fraction of cases. Genetic testing for these genes is
not yet available.

Some inherited genes increase risk for more than one type of cancer. For example, inherited mutations of
the BRCA1 or BRCA2 genes are the reason that breast and ovarian cancers are much more common in
some families. The presence of these gene mutations may also increase prostate cancer risk in some
men, but they are responsible for a very small percentage of prostate cancer cases.

Diet

Men who eat a lot of red meat or who have a lot of high-fat dairy products in their diet appear to have a
slightly higher chance of developing prostate cancer. These men also tend to eat fewer fruits and
vegetables. Doctors are not sure which of these factors is responsible for increasing risk.

Some studies have suggested that men who consume a lot of calcium (through diets or supplements)
may have a higher risk of developing advanced prostate cancer. Most studies, however, have not found
such a link with the levels of calcium commonly consumed in the average diet, and it’s important to note
that calcium is known to have other important health benefits.

Several substances, including lycopenes (found in high levels in some fruits and vegetables, such as
tomatoes, pink grapefruit, and watermelon), vitamin D, vitamin E, and the mineral selenium may lower
prostate cancer risk. Studies are now underway to assess whether these substances actually reduce risk.

Until such studies are completed, the best advice to lower prostate cancer risk is to eat fewer red meats
and high-fat dairy products and to eat 5 or more servings of vegetables and fruits each day. This may also
reduce the risk of several other cancers, as well as other health problems such as heart disease.

Vasectomy

Some earlier studies suggested that men who have had a vasectomy (surgery to make men infertile) may
have a slightly increased risk for prostate cancer, but this link has not been consistently found. Among the
studies that noticed an increase in risk, some found this risk to be highest in men who were younger than
35 when they had a vasectomy.

Research to resolve this issue is still in progress. However, most recent studies have not found any
increased risk among men who have had this operation, and fear of an increased risk of developing
prostate cancer should not be a reason to avoid a vasectomy.

Genetic epidemiology of prostate cancer

Description

The objective of the present project is to investigate the genetic epidemiology of

prostate cancer. In order to do this we will recontact prostate cancer cases
originally interviewed from our original case control study of diet and physical
activity, who had reported one or more first or second degree relatives with
prostate cancer. Detailed objectives will include:

1. to explore gene-environment interactions by comparing cases with one or

more first or second degree relatives with prostate cancer, and cases from
our original study who have no first or second degree relatives with
prostate cancer, with controls using previously reported personal
characteristics (diet, physical activity, body size) while stratifying by
number and type of relative with prostate cancer;
2. to compare the observed incidence of the major cancers in families of
prostate cancer cases with one or more first or second degree relatives
with prostate cancer to that expected in the normal population;
3. to describe the patterns of reported prostate cancer occurrence in families
and determine if they are consistent with the existence of one or more
predisposing genes; and
4. to identify high-risk families, defined as families with 3 or more
pathologically or clinically confirmed cases of prostate cancer (including
the proband) among first and second degree relatives:
a. within these high-risk families to obtain food samples from living
affected members and their first degree relatives, and paraffin
sections of normal and tumour tissue from deceased affected
relatives when available, in order to find genetic markers that co-
segregate with prostate cancer and thus identify candidate loci for
predisposing genes, and
b. to store serum and DNA from members of high-risk families for
future hormonal and genetic analysis when specific loci and or
genes have been identified.

[Etiology of prostate cancer and significance of screening for early

prostate cancer]
[Article in Japanese]

Imai K, Fukabori Y, Yamanaka H.

Dept. of Urology, Gunma University School of Medicine, Japan.

The incidence and mortality rate of prostate cancer in Japan are lower than in Western
countries. Though studies of migrating populations would suggest that dietary or
environmental factors may influence the etiology of the disease. The Westernized
lifestyle after the Second World War may have influenced the increasing incidence of
this disease in Japan. The screening by prostate specific antigen (PSA) on an
asymptomatic healthy population can detect early prostate cancer. It is expected that
the mortality may be decreased through such a system. However, some scientists
hesitate to perform an aggressive program of early detection because of the possibility
of latent cancer detection, the difficulty of distinguishing between clinically important
and unimportant cancer, a high false positive rate to detect early stage cancer, and the
lack of well-executed randomized prospective studies. Current clinical studies of the
prostate cancer have demonstrated that the unimportant cancer detection rate by PSA
was less than 10%. When a 4.0 ng/ml PSA cut-off value is applied for early detection,
the false positive rate is approximately 80%. It is important to make subjects
examined by the screening program aware of its the meaning. However, there is not a
complete and cost-effective diagnostic modality to detect early prostate cancer.
Moreover, it is confirmed that radical prostatectomy improves survival, but it has not
been confirmed to improve the mortality based on population. We propose that well-
executed randomized studies by the end point of the survival, cancer death rate, cost
effective, QOL and etc. are urgently needed.

The etiology of prostate cancer: what does the epidemiology suggest?

Ross RK, Paganini-Hill A, Henderson BE.

The two most important demographic characteristics of prostate cancer in Los

Angeles are the high rates among blacks, which are two times those among whites
and four times those among Asians, and the rapid increase in rates with age after age
40. Despite the high rates among blacks, a birth cohort analysis indicates that
mortality rates among black men born after 1900 have decreased. In this report,
epidemiologic and experimental evidence supporting each of three etiologic
hypotheses--industrial exposure to cadmium, sexual transmission by an infectious
agent, and endocrine factors--are reviewed. Evidence from descriptive data in Los
Angeles suggests that only a small portion of cases might be attributable to industrial
exposures. In a cohort study of Catholic priests, we found no deficit of prostate cancer
mortality, strong evidence against sexual transmission of the disease. Experimental
evidence and a limited amount of human data support an endocrine hypothesis.
Preliminary results of a case-control study of prostate cancer are presented, but these
results are unable to distinguish among these hypotheses further. This study finds a
substantial protective effect of vasectomy, an event that is accompanied by reduced
prostatic function and size, but this result is thus far statistically insignificant.
Genetic predisposition to prostate cancer: possible explanations for
ethnic differences in risk.

Shibata A, Whittemore AS.

Department of Health Research and Policy, Stanford University School of Medicine,

California 94305-5092, USA.

BACKGROUND: It seems unlikely that the large ethnic differences in prostate cancer
risk can be explained completely by ethnic differences in diet or other lifestyle
characteristics. Instead, the differences may be due to ethnic variation in endogenous
factors, such as androgen metabolism or inherited susceptibility. METHODS: We
have reviewed the literature for evidence and support of ethnic variation in genetic
susceptibility to prostate cancer as a reason for the ethnic differences in rates.
RESULTS: We distinguish two types of ethnic variation: 1) variation in the
prevalence of certain alleles of specific genes that confer modestly increased risk.
Such variation might be reflected in ethnic differences in serum levels of androgens,
their metabolites, or indicators of metabolism in the prostate; 2) variation in the
prevalence of rare germline mutations conferring substantially increased risk. Such
variation would be reflected in ethnic differences in familial aggregation of prostate
cancer. We discuss the evidence in support of each of these two possibilities.
CONCLUSIONS: Ethnic variation in polymorphic alleles of genes associated with
modest fluctuations in risk could explain a large proportion of the ethnic difference in
cancer risk. In contrast, rare mutations associated with substantially increased risk are
likely to account for a smaller fraction of these differences.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

Genetic predisposition to prostate cancer.

Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK.

Prostate cancer has been known to run in families for about 40 years and
epidemiological studies have demonstrated an increased risk to close relatives of
cases. This risk rises markedly when the closeness and number of cases in a cluster
increases. There has been considerable debate about the genetic model, in particular
whether there is a commoner lower penetrance (moderately increased risk of the
disease due to the gene(s)) in addition to contribution from high risk genes. For the
first time, molecular results are starting to emerge, indicating the location of high risk
genes. These have shown that there is evidence for more than one site of a high risk,
gene two sites on chromosome 1 and one on chromosome X. These do not account for
all clusters of prostate cancer cases and further genes remain to be discovered. This
article also outlines the contribution of the numerous collaborators in the British
Prostate Group to the UK Familial Prostate Cancer Study.

Inheritance of Prostate Cancer Risk

Evidence for inherited forms of prostate cancer can be found in several US and international
studies.[21][25][38][39][40][41] In 1956 it was first noted that men with prostate cancer reported a higher
frequency of the disease among relatives than did controls.[42] Shortly thereafter, it was reported that
deaths due to prostate cancer were increased among fathers and brothers of men who died of prostate
cancer versus controls who died of other causes.[43]

Many types of epidemiologic studies (case control, cohort, twin, family) strongly suggest that prostate
cancer susceptibility genes exist in the population. An analysis of monozygotic and dizygotic twin pairs
in Scandinavia concluded that 42% (CI 29%-50%) of prostate cancer risk may be accounted for by
heritable factors.[44] This is in agreement with a previous US study that showed a concordance of 7.1%
between dizygotic twin pairs compared with a 27% concordance between monozygotic twin pairs.[45] In
1992, the first segregation analysis was performed using families from 740 consecutive probands who
had radical prostatectomies between 1982 and 1989. The study results suggested that familial
clustering of disease among men with early-onset prostate cancer was best explained by the presence
of a rare (frequency of 0.003) autosomal-dominant , highly penetrant allele(s) .[21] Hereditary prostate
cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55
years or younger).

Subsequent segregation analyses generally agreed with the conclusions but differed in the details
regarding frequency, penetrance , and mode of inheritance.[46][47][48] For example, a study of 4,288 men
who underwent radical prostatectomy during 1966-1995 found that the best fitting genetic model of
inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In
this study, the lifetime risk for carriers was estimated to be 89% by age 85 compared with 3.9% of
noncarriers.[45] This study also suggested the presence of genetic heterogeneity , as the model did not
reliably predict prostate cancer risk in first-degree relatives of probands who were diagnosed at age 70
years or older. More recent segregation analyses have concluded that there may be multiple genes
associated with prostate cancer [49][50][51][52] in a pattern similar to other adult-onset hereditary cancer
syndromes , such as those involving the breast, ovary, colorectum, kidney, and melanoma.

Prostate Cancer Susceptibility Loc

Like most cancers, prostate cancer is a complex neoplastic disorder in which disease initiation is the
result of an interaction between genetic and nongenetic factors. The identification of causative genes for
prostate cancer, however, has been elusive in spite of segregation analyses of prostate cancer families
that support the existence of 1 or more hereditary prostate cancer genes.[1][2][3][4][5][6][7][8] Several candidate
loci have been identified by performing genome-wide linkage analysis studies in high-risk families, but
confirmation of these proposed susceptibility loci from subsequent studies has often been lacking.
Further, some prostate cancer susceptibility genes have been characterized by positional cloning, but
follow-up studies have not yet demonstrated that any of these loci contribute to a significant number of
high-risk prostate cancer families. While the goal of linkage analysis is to identify the chromosomal
location of prostate cancer susceptibility genes none of the putative genes in these regions identified to
date have been widely accepted as clinically useful. Examples of loci that have been identified in studies
of high-risk families are discussed below and are summarized in Table 2.

Prostate Cancer Linkage Studies

The recognition that prostate cancer clusters within families has led many investigators to collect
multiplex families with the goal of localizing prostate cancer susceptibility genes through linkage studies.
Despite the extensive collection of prostate cancer families and the formation of a collaborative research
group (the International Consortium for Prostate Cancer Genetics [ICPCG]), however, the identification
of prostate cancer genes has been exceedingly difficult. A review of 8 prostate cancer linkage studies
that evaluated a total of 4,600 cases of prostate cancer from 1,293 kindreds found several
methodological differences. The authors suggest that differences in populations, enrollment criteria, and
underlying genetic models used for each analysis may account for the lack of consistency between
linkage studies.[9] The following discussion highlights both the clinical and research issues leading to this
complexity.

Linkage studies are typically performed on high-risk extended pedigrees in which multiple cases of a
particular disease occur through vertical generations. The analysis provides statistical evidence for or
against a chromosomal region's harboring susceptibility loci based on more than 400 genetic markers
across the genome. This genome scan statistically compares the genotypes between affected and
unaffected individuals. Thus, the analysis "links" the disease to specific markers in a known
chromosomal location. Because the risk for prostate cancer is influenced by both age of onset in
affected relatives and number of relatives affected, the lack of family information about prostate cancer
can limit the overall analysis. Further, prostate cancer is a late-onset disease typically affecting men
older than 60 years, making the identification and collection of DNA samples from older generations
difficult because many affected men may be deceased or unavailable for study due to advanced age.
Understanding the transmission of disease alleles is also complicated by the fact that the phenotype of
a prostate cancer susceptibility gene (if one exists) in women is unknown.

Because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer
linkage studies have not used consistent criteria for enrollment.[9] One criterion that has been proposed
is the Hopkins Criteria that provides a working definition of hereditary prostate cancer families.[10] The 3
criteria are kindreds with prostate cancer in the following:

1. 3 or more first-degree relatives (father, brother, son).

2. 3 successive generations of either the maternal or paternal lineages, and/or
3. At least 2 relatives affected at age 55 years or younger.

Families need to fulfill only 1 of these criteria to be considered to have hereditary prostate cancer
(HPC). Validity of these research criteria has not been confirmed for clinical management and must
await identification of specific prostate cancer susceptibility genes. Using these criteria, a study has
shown that approximately 5% of men in a large surgical series will be from a family with HPC.[10]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the
context of family studies. As a man's lifetime risk of prostate cancer is 1 in 6, it is possible that families
under study have men with both inherited and sporadic prostate cancer.[11] Thus men who do not inherit
the prostate cancer susceptibility gene that is segregating in their family may still develop prostate
cancer. Currently there are no clinical or pathological features of prostate cancer that will allow
differentiation between inherited and sporadic forms of the disease. Similarly, there are no definitive data
regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate
loci. Measurement of the serum PSA has been used inconsistently in evaluating families used in linkage
analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased
by the use of serum screening as the rates of prostate cancer in families will differ between screened
and unscreened families.

Hereditary Prostate Cancer 1

The results of a genome-wide scan of 91 high-risk prostate cancer families meeting the Hopkins criteria
from the United States and Sweden suggested the presence of a major prostate cancer susceptibility
locus at chromosome 1q24,[12] designated HPC1. Assuming genetic heterogeneity (i.e., that it is likely
that only a subset of these 91 families carry an HPC1 mutation ), the odds favoring the presence of this
gene are nearly 1 million to 1. The genetic evidence supporting the existence of HPC1 was confined to
35% of the 91 families. This subgroup was characterized clinically by having more than 5 affected family
members and an average age at prostate cancer diagnosis younger than 65 years. Further analyses of
families that are genetically linked to HPC1 revealed the following characteristics:

• Younger age at diagnosis.

• Higher tumor grade (Gleason score).
• More advanced stage at diagnosis.[13][14]
Despite the strength of the initial results,[12] subsequent studies have often failed to confirm the
linkage.[15][16][17][18] Nevertheless, confirmatory results were obtained in 2 studies in the United States that
involved 59 and 92 families.[19][20] Linkage evidence in these reports was stronger among families in
which prostate cancer was diagnosed earlier in life (<67 years) or that fit the Hopkins definition of HPC.
In an analysis of 41 families from Utah, in which the mean number of affected men per family was large
(10.7), linkage with 1q24-25 was confirmed.[21] The ICPCG pooled data from 772 families in North
America, Australia, Finland, Norway, Sweden, and the United Kingdom and obtained some evidence of
linkage at 1q24.[22] The estimated percentage of familial prostate cancer families explained on the basis
of this putative gene locus was 6%. Stronger evidence of linkage was seen among families with a male-
to-male pattern of inheritance. Modest evidence for linkage to this region was also identified on a
genome-wide scan of 188 families from Johns Hopkins,[23] including 51 kindreds examined in the initial
positive linkage study.[12] A study of 33 African American families demonstrated some evidence in
support of prostate cancer linkage to markers that map to several HPC candidate regions. [24]

Data suggest that the RNASEL gene at 1q25 may be the molecular basis of the prostate cancer
susceptibility locus HPC1. The gene encodes an endoribonuclease that is a member of the interferon
regulated 2-5A system. Deleterious germline RNASEL mutations were detected in 2 out of 8 families
with prostate cancer linkage to 1q24-25 markers. Follow-up studies by several groups, however, have
not identified a significant number of RNASEL germline variants among families with hereditary prostate
cancer.[25][26] In a study of Finnish men with prostate cancer, a stop mutation, E265X, was found in 4.3%
of the men from HPC families compared with 1.8% of controls.[27] A founder frameshift mutation in
RNASEL (471delAAAG) was identified in 4% of Ashkenazi individuals.[28] The frequency of this mutation
was higher in men with prostate cancer than in elderly male controls (6.9% versus 2.4%, odds ratio
(OR) 3.9; 95% confidence interval (CI) 0.6-15.3; P = .17). Significant associations were noted between
the common RNASEL polymorphism R462Q and familial prostate cancer.[25] This substitution results in a
3-fold reduction in RNASEL activity.[29] A Swedish population-based case-control study examined the
prevalence of E265X and other variants in the RNASEL gene. There were no differences for the E265X
truncating mutation between the 780 controls (1.9%), 1,204 sporadic prostate cancer cases (1.9%), or
350 familial/HPC prostate cancer cases (1.4%).[30] Further, this group did not find significant differences
between cases and controls for the R462Q variant. In summary, there is evidence both for and against
rare and common RNASEL variants contributing to a proportion of familial prostate cancer cases,
although larger studies are required to more carefully delineate both the clinical and biologic implications
of germline RNASEL variants.

Hereditary Prostate Cancer X

A prostate cancer susceptibility locus (designated HPCX) has been mapped to the X chromosome by
using a set of high-risk prostate cancer families from the United States, Finland, and Sweden.[41] In this
initial report, linkage to a hypothesized gene located at Xq27-28 was predicted to account for 16% of
prostate cancer among the 360 families that were analyzed. Analytic epidemiology studies have shown
a higher relative risk of prostate cancer among men with an affected brother versus men with an
affected father, a finding that supports the possibility of a prostate cancer susceptibility locus on the X
chromosome.[42] However, this pattern is also consistent with an autosomal recessive mode of
inheritance or environmental factors. Follow-up HPCX linkage studies have shown some evidence in
support of the existence of this locus,[35][43][44][45] and an ICPCG meta-analysis is in process.

CAPB
Many cancer susceptibility genes increase the risk for more than 1 type of malignancy. For example,
BRCA1 mutations increase a woman's chance of developing both breast and ovarian cancer. In this
regard, a set of prostate cancer families were identified that have 1 or more cases of primary brain
cancer.[46] In this set of 12 families, prostate cancer linkage to 1p36 markers was observed. This
hypothetical gene locus has been named CAPB. Loss of heterozygosity of this same genetic region was
previously observed in sporadic brain cancers, suggesting there is a tumor suppressor gene in this
genomic interval. Other groups have not consistently confirmed prostate cancer linkage to CAPB in
families with both brain and prostate cancers.[33][47] Further, there is evidence for linkage to 1p36 in 1
study of 207 prostate cancer families, considering as affected only those individuals with prostate
cancer. This was particularly evident in families with early-onset disease in which the prostate cancer
was diagnosed before age 59 years.[47] This raises the possibility that CAPB mutations may contribute to
prostate cancer in a site-specific manner.
ELAC2/HPC2
The ELAC2/HPC2 prostate cancer predisposition gene on chromosome 17p was cloned after a
genome-wide scan of high-risk families from Utah.[48] Two segregating germline mutations were
identified among these multiplex prostate cancer families. Neither linkage evidence to 17p11 markers
nor rare ELAC2/HPC2 variants were found in other sets of multiplex families.[49] The ELAC2/HPC2 gene
from 300 men from 150 prostate cancer families (with 3+ cases of prostate cancer) was sequenced and
identified only 1 stop codon and 5 additional missense mutations.[50]

Two common variants in ELAC2/HPC2 have been extensively studied for their potential contribution to
prostate cancer susceptibility. In a clinic-based study of 350 prostate cancer cases and 266 age-
matched and race-matched controls, it was reported that men who carry both of 2 common
polymorphisms in the ELAC2/HPC2 gene experience a modest increase in risk of prostate cancer (OR
2.4, 95% CI, 1.1-5.3).[51] Many additional studies have been reported, 6 of which have been pooled in a
meta-analysis.[52] The authors suggest that the use of unscreened controls in case-control studies
results in the inclusion of a significant number of men with prostate cancer cases among subjects who
are classified as controls. This misclassification error will bias association studies toward the null. If for
example, in the ELAC2/HPC2 meta-analysis, exclusion of data from association studies in which
prostate cancer screening was performed in controls resulted in a positive association between the
Thr541 substitution and prostate cancer risk (OR=1.8, 95% CI, 1.2-2.7, P = .0029). To the extent that
misclassification bias is operating in this series, the reported odds ratio may underestimate the strength
of the observed association. Studies using population-based sampling might be expected to clarify the
potential role of common ELAC2/HPC2 polymorphisms in prostate cancer. An Australian study found no
significant association between ELAC2/HPC2 and prostate cancer.[53] Furthermore, these authors
pooled their new data with those from 7 published studies; their meta-analysis strengthened the
conclusion that no association exists.

HPC20
Evidence for yet another prostate cancer susceptibility locus on chromosome 20, which has been
termed HPC20, was reported.[35][54] In stratified analyses, the group of patients with the strongest
evidence of linkage to this locus were the families with fewer than 5 family members affected with
prostate cancer, a later average age at diagnosis, and no male-to-male transmission, a pattern distinctly
different from that reported for HPC1. Some evidence of prostate cancer linkage to HPC20 has been
observed in 2 independent sets of families,[55][56] although the candidate genomic interval remains large.
However, a combined linkage analysis of 1,234 pedigrees performed by the International Consortium for
Prostate Cancer Genetics failed to replicate linkage of hereditary prostate cancer to 20q13 markers.[57]
In this report, the original 158 Mayo families that were used to identify HPC20 had a maximum
heterogeneity logarithm of the odd (LOD) score under a recessive model of 2.78 whereas the remaining
1,076 families has a maximum heterogeneity LOD score of 0.06 using the same model. These data
suggest that if HPC20 truly exists, it may only account for a small fraction of all hereditary prostate
cancers.

8p Loci
Chromosome 8p is commonly deleted in prostate cancer; consequently many groups have focused on
using deletion mapping in an attempt to localize 1 or more tumor suppressor genes in this region.
Several genome-wide scans have provided modest evidence of prostate cancer linkage to markers that
map to 8p.[23][36][58] Evidence has been reported that both rare and common variants in the macrophage
receptor 1 gene (MSR1) at 8p22 are associated with prostate cancer susceptibility.[59][60] Case control
studies examining an association between these alleles and prostate cancer, however, did not show
significant findings.[61][62][63] Germline variants of the LZTS1 gene, also at 8p22, have been reported to be
associated with sporadic prostate cancer.[64]

Other Loci
Genome-wide linkage studies of families with prostate cancer have identified several
other loci that may harbor prostate cancer susceptibility genes, emphasizing the
underlying complexity and genetic heterogeneity of this cancer. The chromosomal
regions with modest-to-strong statistical significance (LOD score of 2 or more)
include the following chromosomes
Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple
prostate cancer-affected individuals. Conflicting evidence exists regarding the linkage to some of the loci
listed above. Data are also limited on the proposed phenotype associated with each loci and the
strength of repeated studies is needed to firmly establish these associations. There is evidence to
suggest that many of these prostate cancer loci account for disease in a small subset of families
consistent with the concept that prostate cancer exhibits locus heterogeneity.

Candidate Clinical Proposed

Gene Location Comments
Gene Testing Phenotype
HPC1 [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] 1q24-25 RNASEL Not Younger age Evidence of
available at prostate linkage is
cancer strongest in
diagnosis families with 5
(<65 years) or more
affected
persons,
young age at
diagnosis,
and male-to-
male
transmission
Higher tumor grade (Gleason Score)
More advanced stage at diagnosis RNASEL
mutations
have been
identified in
some 1q-
linked
families
PCAP [9][12][16][23][31][32][33][34][35][36][37][38][39][40] 1q42.2-43 None Not Younger age Evidence of
available at prostate linkage
cancer strongest in
diagnosis European
(<65 years) families
HPCX [35][41][42][43][44][45] Xq27-28 None Not Unknown May explain
available observation
that an
unaffected
man with an
affected
brother has a
higher risk
than an
unaffected
man with an
affected father
CAPB [33][46][47] 1p36 None Not Younger age Strongest
available at prostate linkage
cancer evidence was
diagnosis initially
(<65 years) described in
families with
both prostate
and brain
cancer, follow-
up studies
indicate that
this locus may
 be associated
specifically
with early-
onset prostate
cancer but not
necessarily
brain cancer
One or more cases of brain cancer
HPC20 [35][54][55][56][57] 20q13 None Not Later age at Linkage
available prostate evidence
cancer strongest in
diagnosis families with
late age at
diagnosis,
fewer affected
family
members, and
no male-to-
male
transmission
(Table2)

Prostate Cancer Treatment Options by Stage

Treatment Options for Stage I Prostate Cancer

Stage I prostate cancer means that your cancer could not be palpated during a digital
rectal exam (DRE) or during a rectal ultrasound. The tumor(s) are too small, and your
prostate cancer has been detected early-- a good thing! It also means that the tumor
cells are of a slow growing type--another good thing!

Specialists will most often recommend the following when you are diagnosed with a
stage I prostate cancer:

• Radical prostatectomy, possibly with radiation therapy after surgery.

• External Beam Radiation Therapy (EBRT).
• Radiation Seed Implant Therapy (Brachytherapy).
• Cryotherapy is also being recommended.

Mortality rates are very similar for each of the above listed treatments, with survival
rates very close to those without prostate cancer history.

When choosing a treatment with your doctor, you should weigh the different side
effects of each option against each other.

Treatment Options for Stage II Prostate Cancer

Stage II prostate cancer generally means that your cancer could be palpated during a
digital rectal exam (DRE) or seen during a rectal ultrasound. The prostate cancer has
not spread outside of the prostate.

Specialists will most often recommend the following when you are diagnosed with a
stage II prostate cancer:
 • Radical prostatectomy, with removal of the lymph nodes of the pelvis. This
may be followed with radiation therapy.
• External Beam Radiation Therapy (EBRT).
• Radiation Seed Implant Therapy (Brachytherapy).
• Cryotherapy is also being recommended.

Treatment Options for Stage III Prostate Cancer

Stage III prostate cancer means that the cancer has extended beyond the prostate
capsule (the outer boundary of the prostate) but has not spread to other organs, or to
the lymph nodes. Specialists will most often recommend the following when you are
diagnosed with a stage III prostate cancer:

• Externalradiation therapy with or without hormone therapy

• Hormone therapy
• Radical prostatectomy
• Watch and wait
• Radiation therapy, hormone therapy, or transurethral resection of the prostate
as palliative therapy to relieve symptoms caused by the cancer
• A clinical trial of radiation therapy, ultrasound-guided cryosurgery, or other
methods of treatment.

• Cryotherapy is also in clinical trial.

Treatment Options for Stage IV Prostate Cancer

Stage IV prostate cancer means that the cancer has extended beyond the prostate
capsule (the outer boundary of the prostate) and has metastasized (spread) to other
distant organs or tissues. Specialists will most often recommend the following when
you are diagnosed with a stage IV prostate cancer:

• Patient may want to consider clinical trials

• Hormone therapy
• Watch and wait
• Radical prstatectomy
• Clinical trial of chemotherapy
• Other methods in clinical trials

http://cancer.about.com/od/prostatecancer/a/treatmentstage.htm