Purpose of This PDQ Summary
Introduction

Risk Factors for Prostate Cancer Family History as a Risk Factor for Prostate Cancer Inheritance of Prostate Cancer Risk

Prostate Cancer Susceptibility Loci

Prostate Cancer Linkage Studies Hereditary Prostate Cancer 1 Prostate Cancer Predisposing Locus Hereditary Prostate Cancer X CAPB ELAC2/HPC2 HPC20 8p Loci 8q BRCA1 and BRCA2 KLF6 AMACR Other Potential Prostate Cancer Genes Other Regions Identified by Linkage Studies Genome-wide Association Studies

Polymorphisms and Prostate Cancer Susceptibility
Interventions in Familial Prostate Cancer

Primary Prevention Screening Treatment

Prostate Cancer Risk Assessment

Risk Assessment and Analysis Genetic Testing

Psychosocial Issues in Prostate Cancer

Introduction Risk Perception Anticipated Interest in Genetic Testing Hereditary Prostate Cancer Families and Screening         Screening behaviors Quality of Life in Relation to Screening for Prostate Cancer Among Individuals at Increased Hereditary Risk

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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of prostate cancer. This summary is reviewed regularly and updated as necessary by the Cancer Genetics Editorial Board ¹.

The following information is included in this summary:

• Family history and other risk factors for prostate cancer.
• Prostate cancer susceptibility loci and polymorphisms associated with prostate cancer risk.
• Risk assessment for hereditary prostate cancer.
• Screening and risk modification for hereditary prostate cancer.
• Psychosocial issues associated with hereditary prostate cancer.

The summary also contains level-of-evidence designations. These designations are intended to help readers assess the strength of the evidence in relation to specific studies or strategies. A description of how level-of-evidence designations are made is described in detail in the PDQ summary Cancer Genetics Overview ².

This summary is intended to provide clinicians a framework for discussing genetic testing, screening, and risk modification options with individuals at risk for hereditary prostate cancer, as well as for making referrals to cancer risk counseling services. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

Introduction

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms ³. When a linked term is clicked, the definition will appear in a separate window.]

The public health burden of prostate cancer is substantial. A total of 186,320 new cases of prostate cancer and 28,660 deaths from the disease are anticipated in the United States in 2008, making it the most frequent nondermatologic cancer among U.S. males.[1] A man’s lifetime risk of prostate cancer is 1 in 6. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patient’s life) is greater than the number of men with clinically detected disease. A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold.[3] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 per 100,000 men. Higher incidence rates are generally observed in northern European countries. African American men, however, have the highest incidence of prostate cancer in the world; within the United States, African American men have a 60% higher incidence rate compared with white men.[4]

These differences may be due to genetic, environmental, and social influences (such as access to health care), which affect the development and progression of the disease.[5] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[6] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular genetics of prostate cancer is still limited. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initial and promotional events under both genetic and environmental influences.[5]

The three most important recognized risk factors for prostate cancer in the United States are:

• Age.
• Race.
• Family history of prostate cancer.

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 19,299 for men younger than 40 years, 1 in 45 for men aged 40 through 59 years, and 1 in 7 for men aged 60 through 79 years, with an overall lifetime risk of developing prostate cancer of 1 in 6.[7]

Endogenous hormones, including both androgens and estrogens, likely influence prostate carcinogenesis. It has been widely reported that eunuchs and other individuals with castrate levels of testosterone prior to puberty do not develop prostate cancer.[8] Some have speculated that higher serum levels of testosterone and lower levels of estrogen result in higher rates of prostate cancer, but this has not been consistently demonstrated in clinical studies. Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[9] including the potential role of the androgen receptor CAG repeat length in exon 1.

Some dietary risk factors may be important modulators of prostate cancer risk; these include fat and/or meat consumption,[10] vitamin E,[11,12] lycopene,[12,13] dairy products/calcium/vitamin D,[14] and selenium.[15] Phytochemicals are plant-derived nonnutritive compounds, and it has been proposed that dietary phytoestrogens may play a role in prostate cancer prevention.[16] For example, Southeast Asian men typically consume soy products that contain a significant amount of phytoestrogens; this diet may contribute to the low risk of prostate cancer in the Asian population. There is little evidence that alcohol consumption is associated with the risk of developing prostate cancer; however, data suggest that smoking increases the risk of fatal prostate cancer.[17] Several studies have suggested that vasectomy increases the risk of prostate cancer,[18] but other studies have not confirmed this observation.[19]

Refer to the PDQ summary on Prevention of Prostate Cancer ⁴ for more information.

As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[20-24] From 5% to 10% of prostate cancer cases are believed to be due primarily to high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[21,25,26] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[22-26]

Although many of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series. The latter are thought to provide information that is more generalizable. The Massachusetts Male Aging Study of 1,149 Boston-area men found a relative risk (RR) of 3.3 (95% confidence interval [CI] of 1.8–5.9) for prostate cancer among men with a family history of the disease.[27] This effect was independent of environmental factors, such as smoking, alcohol use, and physical activity. Further associations between family history and risk of prostate cancer were characterized in an 8-year to 20-year follow-up of 1,557 men aged 40 through 86 years who had been randomly selected as controls for a population-based case-control study conducted in Iowa from 1987 through 1989. At baseline, 4.6% of the cohort reported a family history of prostate cancer in a brother or father, and this was positively associated with prostate cancer risk after adjustment for age (RR = 3.2; 95% CI, 1.8–5.7) or after adjustment for age, alcohol, and dietary factors (RR = 3.7; 95% CI, 1.9–7.2).[28]

A meta-analysis of 33 epidemiologic studies provides more detailed information regarding risk ratios related to family history of prostate cancer. Risk appears to be greater for men with affected brothers (RR = 3.4; 95% CI, 3.0–3.8) than for men with affected fathers (RR = 2.2; 95% CI, 1.9–2.5). Although the reason for this difference in risk is unknown, possible hypotheses include X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives: RR was 2.6 (95% CI, 2.3–2.8) for one first-degree relative and 5.1 (95% CI, 3.3–7.8) for two or more first-degree relatives, but RR was only 1.7 (95% CI, 1.1–2.6) for an affected second-degree relative. Risk was influenced by age at prostate cancer diagnosis in this meta-analysis: RR was 3.3 (95% CI, 2.6–4.2) for diagnosis before age 65 years, versus a RR of 2.4 (95% CI, 1.7–3.6) for diagnosis at age 65 years or older.[29]

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family Cancer Database warrant special comment, as they are derived from a resource that contains 10.2 million individuals, among whom there are 182,000 fathers and 3,700 sons with medically verified prostate cancer.[30] The size of this data set, with its near complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. The familial standardized incidence ratios (SIRs) for prostate cancer were 2.4 (95% CI, 2.2–2.6), 3.8 (95% CI, 2.7–5.0), and 9.4 (95% CI, 5.8–14.0) for men with prostate cancer in their fathers only, brothers only, and both father and brother, respectively. The SIRs were even higher if the affected relative was diagnosed with prostate cancer before age 55 years. A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5%, 15%, and 30% by ages 60, 70, and 80 years, respectively, compared with 0.45%, 3%, and 10% at the same ages in the general population. The risks were higher still if the affected father was diagnosed before age 70 years.[31] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three groups, respectively, yielding a total PAF of 11.6%; approximately 11.6% of all prostate cancer in Sweden can be accounted for on the basis of these familial risk factors.

The risk of prostate cancer may also increase in men who have a family history of breast cancer. Approximately 9.6% of the Iowa cohort had a family history of breast and/or ovarian cancer in a mother or sister at baseline, and this was positively associated with prostate cancer risk (age-adjusted RR = 1.7; 95% CI, 1.0–3.0; multivariate RR = 1.7; 95% CI, 0.9–3.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR = 5.8; 95% CI, 2.4–14.0).[27] Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[27,32] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[33] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the suggested increase in the risk of prostate cancer among men with BRCA1/2 mutations in the setting of hereditary breast/ovarian cancer.[34,35] (Refer to the BRCA1 and BRCA2 ⁶ subsection of the Prostate Cancer Susceptibility Loci ⁷ section of this summary for more information.)

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African Americans, whites, and Asian Americans in the United States and Canada (Los Angeles, San Francisco, Hawaii, Vancouver, and Toronto),[36] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence rates were somewhat lower among Asian Americans as compared with African Americans or whites. A positive family history was associated with a twofold to threefold increase in risk in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.9–3.3) with adjustment for age and ethnicity.[36]

Evidence for inherited forms of prostate cancer can be found in several U.S. and international studies.[21,25,37-40] It was first noted in 1956 that men with prostate cancer reported a higher frequency of the disease among relatives than did controls.[41] Shortly thereafter, it was reported that deaths from prostate cancer were increased among fathers and brothers of men who died of prostate cancer versus controls who died of other causes.[42]

Refer to the PDQ Prevention of Prostate Cancer ⁴ summary for more information about risk factors for prostate cancer in the general population.

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.[43] This is in agreement with a previous U.S. study that showed a concordance of 7.1% between dizygotic twin pairs compared with a 27% concordance between monozygotic twin pairs.[44] The first segregation analysis was performed in 1992 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.[45-47] A study of 4,288 men who underwent radical prostatectomy between 1966 and 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 years compared with 3.9% for noncarriers.[44] 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 [48-51] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (<66 years) compared with noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[52]

References

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26. Cannon L, Bishop DT, Skolnick M, et al.: Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv 1 (1): 47-69, 1982. 
    
    
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29. Zeegers MP, Jellema A, Ostrer H: Empiric risk of prostate carcinoma for relatives of patients with prostate carcinoma: a meta-analysis. Cancer 97 (8): 1894-903, 2003.  [PUBMED Abstract]
    
    
30. Hemminki K, Czene K: Age specific and attributable risks of familial prostate carcinoma from the family-cancer database. Cancer 95 (6): 1346-53, 2002.  [PUBMED Abstract]
    
    
31. Grönberg H, Wiklund F, Damber JE: Age specific risks of familial prostate carcinoma: a basis for screening recommendations in high risk populations. Cancer 86 (3): 477-83, 1999.  [PUBMED Abstract]
    
    
32. Damber L, Grönberg H, Damber JE: Familial prostate cancer and possible associated malignancies: nation-wide register cohort study in Sweden. Int J Cancer 78 (3): 293-7, 1998.  [PUBMED Abstract]
    
    
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34. Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994.  [PUBMED Abstract]
    
    
35. Gayther SA, de Foy KA, Harrington P, et al.: The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 60 (16): 4513-8, 2000.  [PUBMED Abstract]
    
    
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38. Spitz MR, Currier RD, Fueger JJ, et al.: Familial patterns of prostate cancer: a case-control analysis. J Urol 146 (5): 1305-7, 1991.  [PUBMED Abstract]
    
    
39. Goldgar DE, Easton DF, Cannon-Albright LA, et al.: Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 86 (21): 1600-8, 1994.  [PUBMED Abstract]
    
    
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42. Woolf CM: An investigation of the familial aspects of carcinoma of the prostate. Cancer 13 (4): 739-744, 1960. 
    
    
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44. Page WF, Braun MM, Partin AW, et al.: Heredity and prostate cancer: a study of World War II veteran twins. Prostate 33 (4): 240-5, 1997.  [PUBMED Abstract]
    
    
45. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998.  [PUBMED Abstract]
    
    
46. Grönberg H, Damber L, Damber JE, et al.: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146 (7): 552-7, 1997.  [PUBMED Abstract]
    
    
47. Verhage BA, Baffoe-Bonnie AB, Baglietto L, et al.: Autosomal dominant inheritance of prostate cancer: a confirmatory study. Urology 57 (1): 97-101, 2001.  [PUBMED Abstract]
    
    
48. Gong G, Oakley-Girvan I, Wu AH, et al.: Segregation analysis of prostate cancer in 1,719 white, African-American and Asian-American families in the United States and Canada. Cancer Causes Control 13 (5): 471-82, 2002.  [PUBMED Abstract]
    
    
49. Cui J, Staples MP, Hopper JL, et al.: Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am J Hum Genet 68 (5): 1207-18, 2001.  [PUBMED Abstract]
    
    
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51. Valeri A, Briollais L, Azzouzi R, et al.: Segregation analysis of prostate cancer in France: evidence for autosomal dominant inheritance and residual brother-brother dependence. Ann Hum Genet 67 (Pt 2): 125-37, 2003.  [PUBMED Abstract]
    
    
52. Pakkanen S, Baffoe-Bonnie AB, Matikainen MP, et al.: Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance. Hum Genet 121 (2): 257-67, 2007.  [PUBMED Abstract]
    
    

Prostate Cancer Susceptibility Loci

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 one or more hereditary prostate cancer genes.[1-8] 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 ¹¹.

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]), the identification of prostate cancer genes has been exceedingly difficult. A review of eight 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 families in which multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals, and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. The statistical power of linkage analysis is affected by:

• Family size and having a sufficient number of family members who volunteer to contribute DNA.
• The number of disease cases in each family.
• Factors related to age at disease onset.
• Gender differences in disease risk.

Because the risk of prostate cancer is influenced by both age at onset in affected relatives and number of relatives affected, the lack of accurate family history information about prostate cancer can limit the overall analysis.

Because a standard definition of hereditary prostate cancer (HPC) 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 HPC families.[10] The three criteria are kindreds with prostate cancer in the following:

1. Three or more first-degree relatives (father, brother, son),
2. Three successive generations of either the maternal or paternal lineages, and/or
3. At least two relatives affected at age 55 years or younger.

Families need to fulfill only one of these criteria to be considered to have 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 prostate-specific antigen (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.

In an effort to clarify the inconsistent linkage results, the ICPCG combined genome-wide linkage data from 1,233 families contributed by ten individual research teams. One analytic approach used the entire set of 1,233 families and five regions of suggestive linkage (logarithm of the odd [LOD] scores between 1.87 and 3.30) were identified: 5q12, 8p21, 15q11, 17q21, and 22q12. Therefore, the pooled analysis did not formally confirm any previously identified chromosomal regions of interest (see below). In the hope that targeting more homogenous family subsets might facilitate gene identification, a second analysis focused on subsets of the 1,233 families sharing common features, such as multiple affected family members or younger age at diagnosis. In 269 families with at least five affected members, significant linkage was detected at 22q12 (LOD score 3.57) and suggestive linkage was also observed at 1q25, 8q13, 13q14, 16p13, and 17q21. In 606 families with members aged 65 years or younger at diagnosis, linkage was suggested at 3p24, 5q35, 11q22, and Xq12.[12] These findings may facilitate prioritization of genomic regions for further study.

One way to address the inconsistency between linkage studies is to require inclusion criteria that defines clinically significant disease (e.g., Gleason grade ≥7, PSA ≥20 ng/mL) in an affected man.[13-15] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[16,17] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[18,19]

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,[20] 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 five 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.[21,22]

Despite the strength of the initial results,[20] subsequent studies have often failed to confirm the linkage.[23-26] Nevertheless, confirmatory results were obtained in two studies in the United States that involved 59 and 92 families.[27,28] 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.[29] 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.[30] 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,[31] including 51 kindreds examined in the initial positive linkage study.[20] 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.[32]

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 two out of eight 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 HPC.[33,34] 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.[35] A founder frameshift mutation in RNASEL (471delAAAG) was identified in 4% of Ashkenazi individuals.[36] The frequency of this mutation was higher in men with prostate cancer than in elderly male controls (6.9% vs. 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.[33] This substitution results in a threefold reduction in RNASEL activity.[37] 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%).[38] Further, this group did not find significant differences between cases and controls for the R462Q variant. A meta-analysis summarized the data from ten case-control studies that contained data on the RNASEL variants E265X, R462Q and D541E. Only the D541E allele was associated with an increased risk of prostate cancer, although the magnitude of the effect was small.[39] In summary, there is evidence both for and against rare and common RNASEL variants contributing to a proportion of familial prostate cancer cases, though larger studies are required to more carefully delineate both the clinical and biologic implications of germline RNASEL variants.

A genome-wide scan using 49 high-risk prostate cancer families of German and French origin resulted in evidence of a prostate cancer predisposition locus on chromosome 1q42.[24] This is believed to be a separate gene from the HPC1 locus at 1q24.[20] Prostate cancer linkage to this locus, which has been designated PCAP, was described in a second set of European prostate cancer families [40] and families with evidence of linkage had an earlier average age at diagnosis (<65 years). PCAP linkage has not been observed in several studies of U.S. and international HPC families.[9,17,31,41-48]

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.[49] 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 (RR) 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;[50] 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,[44,51-53] and an ICPCG meta-analysis is in process. Using linkage disequilibrium analysis, a specific haplotype in the Xq27-28 region of HPCX was found to be significantly associated with X-linked prostate cancer in Finnish families.[54] This finding was confirmed in a case control training set (292 cases and controls) and replicated in independent test subjects (215 cases and controls). The Xq27 haplotype extended from rs5907859 to rs1493189, and was associated with prostate cancer (OR = 3.41; 95% CI, 1.04–11.17; P = 0.034).[55]

Many cancer susceptibility genes increase the risk for more than one 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 who have one or more cases of primary brain cancer was identified.[56] 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 (LOH) of this same genetic region was previously observed in sporadic brain cancers, suggesting that 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.[42,57] Further, there is evidence for linkage to 1p36 in one 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.[57] This raises the possibility that CAPB mutations may contribute to prostate cancer in a site-specific manner.

The ELAC2/HPC2 prostate cancer predisposition gene on chromosome 17p was cloned after a genome-wide scan of high-risk families from Utah (Table 3) ¹².[58] 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.[59] The ELAC2/HPC2 gene from 300 men from 150 prostate cancer families (with three or more cases of prostate cancer) was sequenced and identified only one stop codon and five additional missense mutations.[60]

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 two 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).[61] Many additional studies have been reported, six of which have been pooled in a meta-analysis.[62] 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. In the ELAC2/HPC2 meta-analysis, if 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), then to the extent that misclassification bias is operating in this series, the reported OR 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.[63] Furthermore, these authors pooled their new data with those from seven published studies; their meta-analysis strengthened the conclusion that no association exists.

Evidence for yet another prostate cancer susceptibility locus on chromosome 20, which has been termed HPC20, has been reported.[44,64] In stratified analyses, the group of patients with the strongest evidence of linkage to this locus were the families with fewer than five 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 two independent sets of families,[65,66] though the candidate genomic interval remains large; however, a combined linkage analysis of 1,234 pedigrees performed by the ICPCG failed to replicate linkage of hereditary prostate cancer to 20q13 markers.[67] In this report, the original 158 Mayo families that were used to identify HPC20 had a maximum heterogeneity 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.

Chromosome 8p is commonly deleted in prostate cancer; consequently, many groups have focused on using deletion mapping in an attempt to localize one 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.[31,45,68] Evidence has been reported that both rare and common variants in the macrophage scavenger receptor 1 gene (MSR1) at 8p22 are associated with prostate cancer susceptibility (Table 3) ¹².[69,70] Case-control studies examining an association between these alleles and prostate cancer, however, did not show significant findings, including a meta-analysis.[71-74] Germline variants of the LZTS1 gene, also at 8p22, have been reported to be associated with sporadic prostate cancer.[75]

A combined analysis of somatic deletions of chromosome 8p in prostate cancer tumor tissue and fine-mapping linkage in multiple-case families has identified two additional regions (8p23.1 and 8p21.3) that are associated with prostate cancer risk.[76]

A linkage peak at chromosome 8q24 was reported in 323 Icelandic prostate cancer families with a peak LOD score of 2.11. Detailed genotyping of this region revealed an association in three case-control populations in Sweden, Iceland, and the United States with allele -8 at marker DG8S737. The population attributable risk for prostate cancer from this allele was 8%. The results were replicated in an African American case-control population, in which the population attributable risk was 16%.[77] Support for the existence of a prostate cancer susceptibility gene at 8q24, specifically in African American men, was also observed using admixture mapping.[78]

A series of studies confirming the association between prostate cancer risk and single nucleotide polymorphism (SNP) rs1447295 has been published.[79-84] Three additional studies evaluating the 8q24 locus have identified a second SNP, rs6983267, which is close to but distinct from rs1447295.[82,85,86] Furthermore, a multiethnic analysis identified five new variants all within this same region, each of which appears to be independently associated with prostate cancer risk. A number of these variants are much more common than rs1447295, suggesting that the proportion of all prostate cancers that may be explained on the basis of genetic variation in this region could be quite large. The well-known differences in prostate cancer risk among diverse population groups also may be related to these findings.[86] These observations are also notable because they occur in a region without known protein-encoding genes, which makes it very difficult to know what the underlying biological mechanism of susceptibility is likely to be. This is likely a recurring situation with genome-wide association studies in which statistically convincing associations are detected, but the truly causal variant and biological mechanism will be difficult to determine, requiring biochemical and other functional studies. These susceptibility alleles are generally associated with OR of 2 or lower and are not immediately clinically relevant.

Refer to the Polymorphisms and Prostate Cancer Susceptibility ¹³ section of this summary for more information on polygenic factors in 8q.

Chromosome 8q24 risk variants have also been characterized in families with HPC. Twelve 8q24 variants from Regions 1, 2, and 3 and one variant from the c-MYC gene were genotyped in 168 probands from HPC families: 1,404 prostate cancer patients from non-HPC families undergoing radical prostatectomy, and 560 control subjects undergoing prostate cancer screening at Johns Hopkins University.[87] Risk alleles from five SNPs in Region 1 (rs1447295, rs4242382, rs7017300, rs10090154, and rs7837688) and alleles from two SNPs in Region 2 (rs6983561 and rs16901979) were significantly more frequent in HPC probands compared with controls. Genotype risk for HPC was also higher for these seven SNPs. Family-based transmission tests found that risk alleles of two SNPs in Region 2 were significantly over-transmitted to affected men in these HPC families. No evidence for linkage to 8q24 was found in these HPC families. Another report from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) evaluated five SNPs and one microsatellite marker found previously to be associated with prostate cancer in 403 non-Hispanic white families with discordant sibling pairs.[88] Using a family-based association test, the minor allele of rs6983561 and the major allele of rs6983267 were found to be preferentially transmitted to affected men. Furthermore, rs6983561 was significantly associated with prostate cancer among men diagnosed before age 50 years and rs6983267 was significantly associated with clinically aggressive disease. These data provide further support for modification of familial prostate cancer risk by variants in 8q24, particularly variants from Region 2.

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. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Studies of male BRCA1 [89] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer, as well as other cancers.[90]

Among male BRCA1 mutation carriers from hereditary breast ovarian cancer kindreds studied by the Breast Cancer Linkage Consortium (BCLC) family set, the risk of prostate cancer was not elevated overall (RR = 1.1; 95% CI, 0.8–1.5); however, the risk was modestly increased (RR = 1.8; 95% CI, 1.0–3.3) among men younger than 65 years.[89]

In contrast, a similar study of male BRCA2 mutation carriers in hereditary breast ovarian cancer kindreds from the BCLC demonstrated that the risk of prostate cancer associated with BRCA2 mutations was increased overall (RR = 4.7; 95% CI, 3.5–6.2). The incidence was also markedly increased among men younger than 65 years at diagnosis (RR = 7.3; 95% CI, 4.7–11.5).[91] Another report from the BCLC suggests that prostate cancer risk may be lower among men with a mutation in the central region of the BRCA2 gene, known as the ovarian cancer cluster region (RR = 0.5; 95% CI, 0.2–1.0).[92]

Several small case series in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi men with prostate cancer.[93-95] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of Ashkenazi (Eastern European) Jewish ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.7%–1.1%) for the 185delAG mutation, 0.3% (95% CI, 0.2%–0.4%) for the 5382insC mutation, and 1.3% (95% CI, 1.0%–1.5%) for the BRCA2 6174delT mutation.[96-99] (Refer to the Major Genes ²⁰ section of the PDQ summary on Genetics of Breast and Ovarian Cancer ²¹ for more information on the BRCA1 and BRCA2 genes.) In these studies, the point estimates of risk were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In a study of more than 5,000 American Ashkenazi Jewish volunteers from the Washington D.C. area (the Washington Ashkenazi Study [WAS]), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among men who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 4%–30%) compared with 3.8% among noncarriers (95% CI, 3.3%–4.4%).[99] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by the age of 70 years; 95% CI, 6%–28%). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

Two studies using similar methods examined the prevalence of Ashkenazi founder mutations among Jewish men with prostate cancer and found an overall positive association between founder mutation status and prostate cancer risk. The first study [100] analyzed 979 consecutive Ashkenazi men with prostate cancer diagnosed in a large region of Israel, and compared the prevalence of founder mutations with age-matched controls from two different sources, the WAS and the Molecular Epidemiology of Colorectal Cancer (MECC) study from Israel. Overall, there was a twofold, statistically significant increase in the risk of prostate cancer among all carriers of founder mutations (OR = 2.1; 95% CI, 1.2–3.6). The magnitude of this risk was similar for BRCA1 and BRCA2 founder mutations, but only the BRCA2 association was statistically significant, when considered separately. This study did not find that mutation carriers developed prostate cancer at an earlier-than-usual age. Further, there was no evidence of unique or specific histopathology findings within the mutation-associated prostate cancers.

The second study [101] tested genomic DNA from 251 Ashkenazi men diagnosed with prostate cancer at their institution for the three common BRCA1/2 founder mutations. Using the control data from the WAS study described above, and after adjusting for age, all founder mutation carriers had a significantly increased risk of prostate cancer (OR = 3.4; 95% CI, 1.6–7.1). When evaluating BRCA1 versus BRCA2 founder mutations separately, no significantly increased risk of prostate cancer was detected for BRCA1 mutation carriers, while the risk among BRCA2 mutation carriers was increased substantially (OR = 4.8; 95% CI, 1.9–12.2).

These two studies support the hypothesis that prostate cancer occurs excessively among carriers of Ashkenazi Jewish founder mutations, and both suggest that the risk may be greater among men with the BRCA2 founder mutation (6174delT) than those with one of the BRCA1 founder mutations (185delAG; 5382insC). The magnitude of the BRCA2-associated risks differ somewhat, undoubtedly because of interstudy differences related to participant ascertainment, calendar time differences in diagnosis, and analytic methods.

Two hundred sixty-three men with prostate cancer diagnosed in the United Kingdom (U.K.) before the age of 56 years underwent testing for BRCA2 mutations.[102] Screening of all coding regions resulted in the identification of six men (2.3%) with protein-truncating BRCA2 mutations, as well as an additional 22 men harboring variants of undetermined significance. Three of the men with deleterious mutations had no family history of prostate, breast, or ovarian cancer. Using estimates of the frequency of BRCA2 mutations in the general U.K. population of 0.14% and 0.12%, the investigators estimated a 23-fold RR of early-onset prostate cancer attributable to BRCA2 mutations (95% CI, 9–57). In a similar study conducted in a U.S. population,[103] 290 men (11% African American and 87% Caucasian) diagnosed with prostate cancer prior to age 55 years, unselected for family history, were screened for BRCA2 mutations. Two protein-truncating BRCA2 mutations were identified for a prevalence of 0.69% (95%CI, 0.08–2.49%). Both mutations were found in Caucasian cases for a prevalence in Caucasians of 0.78% (95%CI, 0.09–2.81%) and a 7.8 (95%CI, 1.8–9.4) RR of prostate cancer in Caucasian BRCA2 mutation carriers. Of the two individuals with a protein truncating mutation, neither reported a family history of breast or ovarian cancer.[103] This study confirms that on rare occasions germline mutations in BRCA2 account for some cases of early-onset prostate cancer, although this is estimated to be less than 1% of early-onset prostate cancers in the U.S.

A founder mutation in BRCA2 (999del5 in exon 9), which was originally described in male and female breast cancer families in Iceland, has been reported to be associated with aggressive prostate cancer in multiple small studies.[104-109] A recent population-based case-control study between BRCA2 999del5 mutation carriers and noncarriers (all of whom had a prostate cancer diagnosis) from the Icelandic Cancer Registry was conducted.[110] Five hundred and twenty-seven out of 596 prostate cancer patients from Iceland with prostate tissues available for pathology review had genetic analysis performed. Thirty patients carrying this BRCA2 mutation were identified and matched to 59 noncarriers by year of diagnosis and year of birth. The results showed that mutation carriers had lower mean age of prostate cancer diagnosis, advanced tumor stage, higher tumor grade, and shorter median survival than noncarriers. Carrying the BRCA2 999del5 mutation was associated with a higher risk of death from prostate cancer (hazard ratio [HR] = 3.42; 95% CI, 2.12–5.51) which remained after adjustment for stage and grade (HR = 2.35; 95% CI, 1.08–5.11). These investigators concluded that the Icelandic BRCA2 999del5 founder mutation was associated with aggressive prostate cancer. Their observations differ from similar analyses of BRCA-related prostate cancer in other population groups and may be specific for the Icelandic founder mutation.

Genomic DNA of 266 subjects from 194 HPC families was screened for BRCA2 mutations using sequence analysis focusing on exonic and preserved regulatory regions. Although a number (n = 31) of nonsynonymous variations were identified, no truncating or deleterious mutations were detected. These investigators concluded that BRCA2 mutations did not significantly contribute to hereditary prostate cancer.[111] A genome-wide scan for HPC using 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence for linkage to chromosome 17q markers.[46] The maximum LOD score in all families was 2.36, and the LOD score increased to 3.27 when only those families with four or more confirmed affected men were analyzed. The linkage peak was centered over the BRCA1 gene. In follow-up, these investigators screened the entire BRCA1 gene for mutations using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers.[112] Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancer was found to have a truncating mutation (3829delT). The remainder of the individuals harbored one or more germline BRCA1 variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence for a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating mutations in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17-linked families.

In another study from the UM-PCGP, common genetic variation in BRCA1 was examined.[113] Conditional logistic regression analysis and family-based association tests were performed in 323 familial and early-onset families, which included 817 men with and without prostate cancer to investigate the association of SNPs tagging common haplotype variation in a 200-kb region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (OR = 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.[46] These findings support further investigation of BRCA1