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Kathleen A. Cooney, M.D.
Many studies over the past two decades have demonstrated
that men with a family history of prostate cancer are at an
increased risk for this disease. For example, Steinberg et
al. (1) compared the family history information from men with
prostate cancer to that provided by their spouses. In this
study, 15% of men with prostate cancer reported that their
father or brother had prostate cancer compared to only 8%
of control subjects. Similar data derived from other epidemiological
studies have confirmed that family history is a significant
risk factor for prostate cancer. Important features of a family
history that may correlate with the magnitude of risk include
1) early age of prostate cancer diagnosis in affected family
members and 2) the total number of affected relatives in a
given family (2).
Does familial prostate cancer have a genetic
The observation that prostate cancer often clusters within
families has led many research teams, including our own, to
collect DNA from prostate cancer families with the goal of
identifying prostate cancer susceptibility genes. However,
there may be other explanations for the finding that prostate
cancer often clusters within families. Prostate cancer is
a very common disease, and men with affected relatives may
be more interested in participating in prostate cancer early
detection programs leading to more diagnoses within a family.
Similarly, first-degree relatives (e.g. brothers) may be exposed
to a common environmental exposure resulting in multiple cases
of prostate cancer within a family. Several research teams
have performed complex segregation analyses to determine the
model that best accounts for the observed clustering of prostate
cancer cases within families. Several analyses performed on
independent sets of families have concluded that there is
likely to be one (or more) highly penetrant prostate cancer
gene(s) that is transmitted in an autosomal dominant fashion.
This gene is likely to account for a significant percentage
of early onset prostate cancer cases but only a small part
of the total burden of the disease (3). Other studies have
suggested that there also may be autosomal recessive and/or
X-linked forms of the disease based on the observation that
an affected brother confers an approximately two-fold excess
risk compared to an affected father (4).
Proposed prostate cancer predisposition genes
To date, four candidate prostate cancer susceptibility genes
have been identified through genetic linkage studies using
a large number of families from throughout the world: HPC1
at 1q24-25 (5), PCAP at 1q42.2-43 (6), CAPB at 1p36 (7), and
HPCX at Xq27-28 (8) (Table 1). HPC1 was first described in
1996; the initial studies performed at the National Human
Genome Research Institute and Johns Hopkins University suggested
that this gene may account for as many as one third of large
prostate cancer families. Furthermore, linkage to this locus
appeared to correlate with early age of prostate cancer diagnosis
and with the presence of five or more affected men within
a family (9). The candidate interval for HPC1 is quite large,
however a number of laboratories are attempting to identify
this gene using positional cloning and other strategies.
The PCAP locus was identified from a whole genome scan using
47 French and German families each containing three or more
men with prostate cancer (6). This putative locus is more
than 50 cM (~ 50 million basepairs) distal to the HPC1 locus.
In the initial report, more significant evidence of linkage
to the PCAP locus was observed in families with an average
prostate cancer onset less than 60 years.
Gibbs et al. (7) found evidence for a prostate cancer susceptibility
locus at 1p36. The initial linkage was observed in a genome
screen of 70 large prostate cancer families. These investigators
noted that allelic deletions involving this same chromosomal
region had been previously described in primary brain cancers.
They therefore hypothesized that families in which both brain
and prostate cancers cosegregate may be more likely to provide
evidence of linkage to this locus. Thus, analysis of nine
families with prostate cancer and at least one case of primary
brain cancer from their dataset suggested linkage to 1p36
Consistent with the genetic epidemiological evidence for
a possible X-linked prostate cancer susceptibility gene, Xu
et al. (8) described linkage to markers that map to Xq27-28.
This locus has been termed HPCX. Three hundred sixty prostate
cancer families from North America, Sweden and Finland were
studied in this report. There was increased evidence for prostate
cancer linkage in men with apparent maternal transmission
of the disease, which is the expected pattern of inheritance
for a prostate cancer susceptibility gene on the X chromosome.
The International Consortium for Prostate Cancer
The identification of prostate cancer susceptibility genes
has turned out to be a particularly difficult problem. This
is in part due to a number of characteristics of prostate
cancer including its late-onset and the high rate of sporadic
prostate cancer in the general population. Linkage studies
published to date indicate that there will likely be multiple
genes that predispose men to prostate cancer, which further
complicates this work. To assist in this endeavor, the National
Cancer Institute has recently supported the formation of the
International Consortium for Prostate Cancer Genetics (ICPCG).
The goal of this research group is to characterize the molecular
basis for the inherited predisposition to prostate cancer
using families from throughout the world. The first collaborative
project was to examine potential evidence for prostate cancer
linkage to HPC1 using a total of 772 families ascertained
by members of the ICPCG from North America, Australia, Finland,
Norway, Sweden and the United Kingdom. As with the previous
smaller studies of HPC1, evidence for prostate cancer linkage
was restricted primarily to the larger families with early
onset prostate cancer (10).
The University of Michigan has been an active participant
in the ICPCG since its inception. Our IRB-approved research
program, which is called the U-M Prostate Cancer Genetics
Project, currently has more than 400 participating families,
each with more than one living family member affected with
prostate cancer. Using this resource, our research team was
the first to confirm the contribution of HPC1 and HPCX to
familial prostate cancer (11,12). We are continuing to enroll
families at this time; for more information contact the U-M
Prostate Cancer Genetics Project at 1-800-723-9170.
- Steinberg GD, Carter BS, Beaty TH, Childs B, and Walsh
PC. Family history and the risk of prostate cancer. Prostate
- Carter BS, Bova GS, Beaty TH, et al. Hereditary prostate
cancer: epidemiologic and clinical features. J Urol 1993;
- Carter BS, Beaty TH, Steinberg GD, Childs B, and Walsh
PC. Mendelian inheritance of familial prostate cancer. Proc
Natl Acad Sci USA 1992; 89:3367-3371.
- Monroe KR, Yu MC, Kolonel LN, et al. Evidence of an x-linked
or recessive genetic component to prostate cancer risk.
Nat Med 1995; 1:827-829.
- Smith JR, Freije D, Carpten JD, et al. Major susceptibility
locus for prostate cancer on chromosome 1 suggested by a
genome-wide search. Science 1996; 274:1371-1374.
- Berthon P, Valeri A, Cohen-Akenine A, et al. Predisposing
gene for early-onset prostate cancer, localized on chromosome
1q42.2-43. Am J Hum Genet 1998; 62:1416-1424.
- Gibbs M, Stanford JL, McIndoe RA, et al. Evidence for
a rare prostate cancer-susceptibility locus at chromosome
1p36. Am J Hum Genet 1999; 64:776-787.
- Xu J, Meyers DA, Freije D, et al. Evidence for a prostate
cancer susceptibility locus on the X chromosome. Nat Genet
20: 175-179, 98 A.D.
- Gronberg H, Xu J, Smith JR, et al. Early age at diagnosis
in families providing evidence of linkage to the hereditary
prostate cancer locus (HPC1) on chromosome 1. Cancer Res
1997; 57: 4707-4709.
- Xu J, and International Consortium for Prostate Cancer
Genetics. Combined analysis of hereditary prostate cancer
linkage to 1q24-25: Results from 772 hereditary prostate
cancer families from the International Consortium for Prostate
Cancer Genetics. Am J Hum Genet 1999 (in press).
- Cooney KA, McCarthy JD, Lange E, et al. Prostate cancer
susceptibility locus on chromosome 1q: a confirmatory study.
J Natl Cancer Inst 1997; 89:955-959.
- Lange EM, Chen H, Brierley K, et al. Linkage analysis
of 153 prostate cancer families over a 30 cM region containing
the putative susceptibility locus HPCX. Clin Cancer Res
1999; 5(12): 4013-402
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