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Please note: This article is part of the Cancer Center's News Archive and is here for historical purposes. The information and links may no longer be up-to-date.

Michigan Oncology Journal Spring 2000

Advances in Our Understanding of the Inherited Predisposition to Prostate Cancer

Kathleen A. Cooney, M.D.
Genetic Counselor

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 component?
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 markers.

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 Genetics
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.

Reference List

  1. Steinberg GD, Carter BS, Beaty TH, Childs B, and Walsh PC. Family history and the risk of prostate cancer. Prostate 1990; 17:337-347.
  2. Carter BS, Bova GS, Beaty TH, et al. Hereditary prostate cancer: epidemiologic and clinical features. J Urol 1993; 150:797-802.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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).
  11. 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.
  12. 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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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.