Genetics of Prostate Cancer

Summary Type: Genetics
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the genetics of prostate cancer, including information about specific genes and family cancer syndromes. The summary also contains information about screening for prostate cancer and research aimed at prevention of this disease. Psychosocial issues associated with genetic testing and counseling of individuals who may have hereditary prostate cancer syndrome are also discussed.

Genetics of Prostate Cancer

Introduction

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. 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 218,890 new cases of prostate cancer and 27,050 deaths from the disease are anticipated in the United States in 2007, 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 lead 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,

Risk Factors for Prostate Cancer

The 3 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 for more information.

Family History as a Risk Factor for Prostate Cancer

As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.^{20,21,22,23,24} 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.^{22,23,24,25,26,}

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 1 first-degree relative and 5.1 (95% CI, 3.3–7.8) for 2 or more first-degree relatives, but RR was only 1.7 (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 2 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 3 groups, 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.

Table 1. Relative Risk Related to Family History of Prostate Cancer

Risk GroupRelative Risk for Prostate CancerCI = Confidence intervalAdapted from Zeegers et al.^29,Brother with prostate cancer diagnosed at any age3.4 (95% CI, 3.0–3.8)Father with prostate cancer diagnosed at any age2.2 (95% CI, 1.9–2.5)One affected first-degree relative diagnosed at any age2.6 (95% CI, 2.3–2.8)One affected second-degree relative diagnosed at any age1.7 (95% CI, 1.1–2.6)Affected first-degree relative(s) diagnosed age <65 years3.3 (95% CI, 2.6–4.2)Affected first-degree relative(s) diagnosed age >65 years2.4 (95% CI, 1.7–3.6)Two or more affected first-degree relatives diagnosed at any age5.1 (95% CI, 3.3–7.8)

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 subsection of the Prostate Cancer Susceptibility Loci 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 2-fold to 3-fold increase in risk in each of the 3 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 US and international studies.^{21,25,37,38,39,40} 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 summary for more information about risk factors for prostate cancer in the general population.

Inheritance of Prostate Cancer Risk

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 US 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.^45,46,47 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 compared with 3.9% of 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 ^48,49,50,51 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,

¹ American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed March 5, 2007.

² Ruijter E, van de Kaa C, Miller G, et al.: Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 20 (1): 22-45, 1999.

³ Stanford JL, Stephenson RA, Coyle LM, et al., eds.: Prostate Cancer Trends 1973-1995. Bethesda, Md: National Cancer Institute, 1999. NIH Pub. No. 99-4543. Also available online. Last accessed March 5, 2007.

⁴ Miller BA, Kolonel LN, Bernstein L, et al., eds.: Racial/Ethnic Patterns of Cancer in the United States 1988-1992. Bethesda, Md: National Cancer Institute, 1996. NIH Pub. No. 96-4104. Also available online. Last accessed March 5, 2007.

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⁶ Hemminki K, Rawal R, Bermejo JL: Prostate cancer screening, changing age-specific incidence trends and implications on familial risk. Int J Cancer 113 (2): 312-5, 2005.

⁷ Jemal A, Murray T, Samuels A, et al.: Cancer statistics, 2003. CA Cancer J Clin 53 (1): 5-26, 2003 Jan-Feb.

⁸ Wu CP, Gu FL: The prostate in eunuchs. Prog Clin Biol Res 370: 249-55, 1991.

⁹ Ross RK, Pike MC, Coetzee GA, et al.: Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res 58 (20): 4497-504, 1998.

¹⁰ Kolonel LN: Fat, meat, and prostate cancer. Epidemiol Rev 23 (1): 72-81, 2001.

¹¹ Heinonen OP, Albanes D, Virtamo J, et al.: Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 90 (6): 440-6, 1998.

¹² Chan JM, Giovannucci EL: Vegetables, fruits, associated micronutrients, and risk of prostate cancer. Epidemiol Rev 23 (1): 82-6, 2001.

¹³ Giovannucci E, Rimm EB, Liu Y, et al.: A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 94 (5): 391-8, 2002.

¹⁴ Chan JM, Giovannucci EL: Dairy products, calcium, and vitamin D and risk of prostate cancer. Epidemiol Rev 23 (1): 87-92, 2001.

¹⁵ Platz EA, Helzlsouer KJ: Selenium, zinc, and prostate cancer. Epidemiol Rev 23 (1): 93-101, 2001.

¹⁶ Barnes S: Role of phytochemicals in prevention and treatment of prostate cancer. Epidemiol Rev 23 (1): 102-5, 2001.

¹⁷ Hickey K, Do KA, Green A: Smoking and prostate cancer. Epidemiol Rev 23 (1): 115-25, 2001.

¹⁸ Bernal-Delgado E, Latour-Pérez J, Pradas-Arnal F, et al.: The association between vasectomy and prostate cancer: a systematic review of the literature. Fertil Steril 70 (2): 191-200, 1998.

¹⁹ Stanford JL, Wicklund KG, McKnight B, et al.: Vasectomy and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 8 (10): 881-6, 1999.

²⁰ Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990.

²¹ Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992.

²² Ghadirian P, Howe GR, Hislop TG, et al.: Family history of prostate cancer: a multi-center case-control study in Canada. Int J Cancer 70 (6): 679-81, 1997.

²³ Stanford JL, Ostrander EA: Familial prostate cancer. Epidemiol Rev 23 (1): 19-23, 2001.

²⁴ Matikaine MP, Pukkala E, Schleutker J, et al.: Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland. Cancer Causes Control 12 (3): 223-30, 2001.

²⁵ Grönberg H, Damber L, Damber JE: Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 77 (1): 138-43, 1996.

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.

²⁷ Kalish LA, McDougal WS, McKinlay JB: Family history and the risk of prostate cancer. Urology 56 (5): 803-6, 2000.

²⁸ Cerhan JR, Parker AS, Putnam SD, et al.: Family history and prostate cancer risk in a population-based cohort of Iowa men. Cancer Epidemiol Biomarkers Prev 8 (1): 53-60, 1999.

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.

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.

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.

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.

³³ Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994.

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.

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.

³⁶ Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995.

³⁷ Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993.

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.

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.

⁴⁰ Braun MM, Caporaso NE, Page WF, et al.: A cohort study of twins and cancer. Cancer Epidemiol Biomarkers Prev 4 (5): 469-73, 1995 Jul-Aug.

⁴¹ Morganti G, Gianferrari L, Cresseri A, et al.: [Clinico-statistical and genetic research on neoplasms of the prostate]. Acta Genet Stat Med 6 (2): 304-5, 1956.

⁴² Woolf CM: An investigation of the familial aspects of carcinoma of the prostate. Cancer 13 (4): 739-744, 1960.

⁴³ Lichtenstein P, Holm NV, Verkasalo PK, et al.: Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343 (2): 78-85, 2000.

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.

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.

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.

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.

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.

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.

⁵⁰ Conlon EM, Goode EL, Gibbs M, et al.: Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset. Int J Cancer 105 (5): 630-5, 2003.

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.

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.

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 .^{1,2,3,4,5,6,7,8} 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]), 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 families in which multiple cases of a particular disease occur through vertical generations. Linkage analysis provides statistical evidence regarding the likelihood that a chromosomal region may harbor a disease susceptibility locus. Linkage analysis statistically compares the genotypes between affected and unaffected individuals. Thus, the analysis links the disease to specific markers in known chromosomal locations. 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 in women (if one exists) 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 one 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 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 10 individual research teams. One analytic approach used the entire set of 1,233 families and 5 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 5 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.^13,14,15 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,

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 1q24,²⁰ 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 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^21,22,

Despite the strength of the initial results,²⁰ subsequent studies have often failed to confirm the linkage.^23,24,25,26 Nevertheless, confirmatory results were obtained in 2 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 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.^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 3-fold 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.

Prostate Cancer Predisposing Locus

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 US and international hereditary prostate cancer families.^{9,17,31,41,42,43,44,45,46,47,48,}

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.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,^44,51,52,53 and an ICPCG meta-analysis is in process.

CAPB

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.⁵⁴ 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.^42,55 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.⁵⁵ 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 (Table 3).⁵⁶ 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.⁵⁷ The ELAC2/HPC2 gene from 300 men from 150 prostate cancer families (with 3 or more cases of prostate cancer) was sequenced and identified only one stop codon and 5 additional missense mutations .^58,

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).⁵⁹ Many additional studies have been reported, 6 of which have been pooled in a meta-analysis.⁶⁰ 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.⁶¹ 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, has been reported.^44,62 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,^63,64 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.⁶⁵ 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 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.^31,45,66 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).^67,68 Case-control studies examining an association between these alleles and prostate cancer, however, did not show significant findings, including a meta-analysis.^69,70,71,72 Germline variants of the LZTS1 gene, also at 8p22, have been reported to be associated with sporadic prostate cancer.⁷³

8q

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 3 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%.⁷⁴ Support for the existence of a prostate cancer susceptibility gene at 8q24, specifically in African American men, was also observed using admixture mapping.^75,

A series of studies confirming the association between prostate cancer risk and single nucleotide polymorphism (SNP) rs1447295 has been published.^76,77,78,79 Three additional studies evaluating the 8q24 locus have identified a second SNP, rs6983267, which is close to but distinct from rs1447295.^79,80,81 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.⁸¹ 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 odds ratios of 2 or lower and are not immediately clinically relevant.

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.

Table 2. Proposed Prostate Cancer Susceptibility Loci

GeneLocationCandidate GeneClinical TestingProposed PhenotypeCommentsHPC1 (OMIM) ^{20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,}1q24–25RNASELNot availableYounger age at prostate cancer diagnosis (<65 years)Evidence of linkage is strongest in families with 5 or more affected persons, young age at diagnosis, and male-to-male transmissionHigher tumor grade (Gleason Score)More advanced stage at diagnosisRNASEL mutations have been identified in some 1q-linked familiesPCAP (OMIM) ^{9,17,20,24,31,40,41,42,43,44,45,46,47,48,}1q42.2–43NoneNot availableYounger age at prostate cancer diagnosis (<65 years)Evidence of linkage strongest in European familiesHPCX (OMIM) ^{44,49,50,51,52,53,}Xq27–28NoneNot availableUnknownMay explain observation that an unaffected man with an affected brother has a higher risk than an unaffected man with an affected fatherCAPB (OMIM) ^42,54,55,1p36NoneNot availableYounger age at prostate cancer diagnosis (<65 years)Strongest linkage evidence was initially 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 cancerOne or more cases of brain cancerHPC20 (OMIM) ^{44,62,63,64,65,}20q13NoneNot availableLater age at prostate cancer diagnosisLinkage evidence strongest in families with late age at diagnosis, fewer affected family members, and no male-to-male transmissionNo male-to-male transmission 8p ^{31,45,66,67,68,69,70,71,72,73,}8p22MSR1Not availableUnknownIn a genomic region commonly deleted in prostate cancer8q ^{74,75,76,77,78,79,80,81,}8q24NoneNot availableUnknownPopulation attributable risk was higher in African American men than in men of European origin

BRCA1 and BRCA2

Studies of male BRCA1 ⁸² and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer, as well as other cancers.⁸³

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.^82,

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).⁸⁴ 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).⁸⁵

Several small case series in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi men with prostate cancer.^86,87,88 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.^89,90,91,92 (Refer to the Major Genes section of the PDQ summary on Genetics of Breast and Ovarian Cancer 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%).⁹² This 4-fold 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 ⁹³ 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 2 different sources, the WAS and the Molecular Epidemiology of Colorectal Cancer (MECC) study from Israel. Overall, there was a 2-fold, 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 ⁹⁴ tested genomic DNA from 251 Ashkenazi men diagnosed with prostate cancer at their institution for the 3 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 2 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.⁹⁵ Screening of all coding regions resulted in the identification of 6 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 UK 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).

Genomic DNA of 266 subjects from 194 hereditary prostate cancer 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.⁹⁶ A genome-wide scan for hereditary prostate cancer using 175 families from the University of Michigan Prostate Cancer Genetics Project 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 4 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.⁹⁷ 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 2 reports is that there is evidence for a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, BRCA1 is likely not a plausible candidate gene due to the lack of deleterious mutations in chromosome 17-linked families.

Thus, the literature suggests that there may be a modest increase in prostate cancer risk among men with one of the Ashkenazi founder mutations, and a more substantial increase in risk among BRCA2 carriers in general; the risk is unclear among BRCA1 mutation carriers. These observations may comprise one of many factors that a man contemplating BRCA mutation testing might consider. Uncertainties regarding screening and management of men at increased risk of prostate cancer make it difficult to encourage BRCA mutation testing solely for prostate cancer risk management. (Refer to the Mutations in BRCA1 and BRCA2 section of the PDQ summary on Genetics of Breast and Ovarian Cancer and the Screening section of this summary for more information about testing for BRCA1 and BRCA2.)

KLF6

The tumor suppressor gene Kruppel-like factor 6 (KLF6), located on chromosome 10p15, is a zinc finger transcription factor potentially associated with prostate cancer risk. Somatic mutations and allelic loss of KLF6 have been found in tumors of several primary neoplasms, including prostate cancer.⁹⁸ A germline mutation in KLF6 (IVS1-27G>A) appears to have a novel mechanism of gene inactivation: generation of alternatively spliced products that antagonize wild-type gene function.⁹⁹ However, data are inconsistent regarding the association of germline mutations in KLF6 and hereditary prostate cancer. A Finnish study of 69 prostate cancer families did not identify an association between KLF6 mutations and prostate cancer susceptibility.¹⁰⁰ The germline KLF6 single nucleotide polymorphism (SNP) described above, IVS1-27G>A, was found to increase the RR of prostate cancer in a US study of 3,411 men (RR = 1.61, P = .01; 95% CI, 1.20–2.16).⁹⁹ However, the prostate cancer risk associated with the IVS1-27G>A SNP was not detected in a study of 300 Jewish prostate cancer families.¹⁰¹ In fact, the A allele, which was previously shown to be more common in US men with prostate cancer and associated with the creation of splice variants, was significantly less common among cases than among controls in this Israeli study (49/804 alleles in cases compared with 55/600 control alleles; P = .030).

Other Potential Prostate Cancer Genes

Individuals who were heterozygous for one of the Nijmegen Breakage Syndrome (NBS) founder mutations identified in Poland may be at increased risk of prostate cancer.¹⁰² NBS is a rare autosomal recessive cancer susceptibility disorder of childhood that is characterized by growth retardation, facial dysmorphism, immunodeficiency, and a predisposition to lymphoma and leukemia in patients with germline biallelic (e.g., homozygous ) mutations. NBS1, located on chromosome 8q, has an important role in DNA repair and is part of the ataxia telangiectasia pathway. Recent observations have suggested that there may be an increased risk of cancer among heterozygous carriers of mutations in a number of genes involved in response to DNA damage, such as xeroderma pigmentosum ¹⁰³ and ataxia telangiectasia.^104,105 Polish investigators analyzed the prevalence of an NBS1 founder mutation in a sample of 56 men with familial prostate cancer, 305 men with sporadic cancer, and control subjects who included men, women, and newborns. Cases with a positive family history were 16 times more likely to be mutation carriers than were controls (P <.0001). LOH was commonly observed in mutation-associated prostate cancers, with preferential loss of the wild-type allele.¹⁰² A collaborative report from 5 groups participating in the ICPCG demonstrated a carrier frequency of 0.22% (2 of 909) for probands with familial prostate cancer and 0.25% (3 of 1,218) for men with sporadic cancer for the founder 657del5 mutation. Although this mutation was not detected in any of the 293 unaffected family members, the low frequency of the founder mutation suggests that NBS1 mutations do not contribute to a significant proportion of prostate cancer cases.^106,

In the first report of possible germline CHEK2 variants in men with prostate cancer, mutations were identified in 4.8% of 578 prostate cancer patients and in none of 423 unaffected men.¹⁰⁷ Nine of 149 multiplex prostate cancer families were also found to have germline CHEK2 mutations. The I157T substitution was detected in equal numbers of cases and controls and thus was felt to likely represent a polymorphism. Functional studies of additional identified variants revealed substantial reductions in CHEK2 protein levels and/or other functional changes that suggest CHEK2 mutations contribute to prostate carcinogenesis.^107,108 Subsequently, Polish investigators sequenced the CHEK2 gene in 140 patients with prostate cancer, and then analyzed the 3 detected variants in a larger series of prostate cancer cases and controls.^109, CHEK2 truncating mutations were identified in 9 of 1,921 controls (0.5%) and in 11 of 690 (1.6%) unselected patients with prostate cancer (OR = 3.4; P = .004). These same mutations were also found in 4 of 98 familial prostate cases (OR = 9.0; P = .0002). The I157T missense variant was also more frequent in men with prostate cancer (7.8%) than in controls (4.8%) (OR = 1.7; P = .03), and was identified in 16% of men with familial prostate cancer (OR = 3.8; P = .00002). LOH was not observed in any of the 5 men with truncating CHEK2 mutations. A follow-up to this study has been reported from Poland with 1,864 prostate cancer patients and 5,496 controls. All three founder mutations as well as a large germline deletion of exons 9 and 10 (5395-bp deletion) were genotyped. The truncating mutation 1100delC was identified in 14 of 1,864 (0.8%) unselected prostate cancer cases and 3 of 249 (1.2%) familial cases (OR = 3.5; P = .002 and OR = 5.6; P = .02, respectively). A significant association with another truncating mutation (IVS2+1G→A) was identified in 5 of 249 (2.0%) familial cases that had the mutation (OR = 5.1; P = .002). The missense mutation I157T was detected in 142 of 1,864 (7.6%) unselected prostate cancer cases and in 30 of 249 (12%) familial cases (OR = 1.6; P <.001 and OR = 2.7; P <.001, respectively). The large deletion in exons 9 and 10 accounted for 4 of 249 (1.6%) familial cases (OR = 3.7; P = .03). Overall, it appears that there are at least four founder mutations in the CHEK2 gene, which account for an estimated 7% of patients with prostate cancer in the Polish population. The most common missense mutation is I157T, and the most common truncating mutation is 5395-bp deletion. These reports suggest that truncating and missense mutations in CHEK2 may play a role in prostate cancer susceptibility.^110,

Table 3 summarizes the candidate genes for prostate cancer susceptibility, their chromosomal location, and availability of clinical testing.

Table 3. Candidate Genes for Prostate Cancer Susceptibility

GeneLocationClinical TestingProposed PhenotypeCommentsBRCA1 (OMIM) ^{82,86,87,88,89,90,91,92,97,111,112,}17q21AvailableYounger age at prostate cancer diagnosis (<65 years); earlier age at diagnosis among carriers of Ashkenazi founder mutations.There is some evidence that men with a BRCA1 mutation may develop prostate cancer at an earlier age.BRCA2 (OMIM) ^{84,85,86,87,88,90,91,92,93,94,95,112,}13q12-13AvailableYounger age at prostate cancer diagnosis (<65 years); earlier age at diagnosis among carriers of Ashkenazi founder mutations.Prostate cancer risk may be lower among men with a mutation in the central region of the BRCA2 gene.RNASEL (OMIM) ^{20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,113,}1q24-25Not availableUnknownRare and common RNASEL variants may contribute to a proportion of familial prostate cancer cases.RNASEL is a candidate gene for HPC1 (Table 2). ELAC2/HPC2 (OMIM) ^{56,57,58,59,60,61,113,}17pNot availableUnknownInfrequent deleterious mutations identified in HPC families in follow-up reports.MSR1 (OMIM) ^{67,68,72,101,113,}8p22Not availableUnknownIn a genomic region commonly deleted in prostate cancer.NBS1 (OMIM)^102,106,8q21AvailableIncreased prostate cancer risk in heterozygotesInfrequent NBS1 mutations, including founder 657del5 variant, in follow-up study.CHEK2 (OMIM) ^107,109,110,22q12.1AvailableUnknownValue of clinical testing for mutations in CHEK2 for prostate cancer risk is not established.KLF6 (OMIM) ^{98,99,100,101,114,}10p15Not availableYounger age at prostate cancer diagnosis (<65 years).

To summarize, studies to date have mapped site-specific prostate cancer susceptibility loci to chromosomes 1q24–25 (HPC1), 1q42.2–43 (PCAP), 1p36 (CAPB), Xq27–2 (HPCX), 20q13 (HPC20), 17p (ELAC2/HPC2), and 8p. Other studies have suggested that prostate cancer may be part of the cancer spectrum of syndromes that include a more diverse set of malignancies, such as seems to be the case for BRCA2 and, perhaps, BRCA1. Both linkage and candidate gene studies have been complicated by the late-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for hereditary prostate cancer, as suggested by both segregation and linkage studies. In this respect, hereditary prostate cancer resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, hereditary nonpolyposis colorectal cancer, hereditary melanoma, and hereditary renal cancer).

Linkage studies may be used to evaluate the possibility that an HPC gene might exist in a particular family, but this analytic approach is currently being done only in the research setting. Until the specific genes and mutations involved are identified, it is difficult to establish the analytical validity of this approach. Without a validated laboratory test, clinical validity and clinical utility cannot be measured. At present, clinical germline mutation testing for hereditary prostate cancer susceptibility is not available.

Other Regions Identified by Linkage Studies

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:

• 2q23 ^31,
• 3p14 ^115,
• 3p24–26 ^12,47,116,
• 4q21 ^31,
• 4q25 ^117,
• 5q11–12 ^12,48,
• 5q35 ^12,
• 6p22.3 ^45,
• 7q ^45,
• 8q13 ^12,
• 9q34 ^31,
• 11q22 ^12,
• 13q14 ^12,
• 15q11 ^12,
• 16p13 ^12,
• 16q23 ^17,
• 17q21–22 ^12,46,117,
• 19p13.3 ^48,
• 22q12 ^12,118,
• Xq12 ^12,

Combined analyses have helped to prioritize candidate regions for further study.^12,

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study on 77 families with four or more affected men. Multipoint HLOD scores greater than or equal to 1.3 and less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score of 1.08) and 22q12 (multipoint HLOD score of 0.91).^12,119,

A study describes a linkage analysis targeting families with clinically aggressive prostate cancer (defined by Gleason grade ≥7, PSA ≥20 ng/mL, and cancer stage). One hundred twenty-three families with 2 or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (heterogeneity LOD [hLOD] score of 2.18) and 22q12.3-q13.1 (hLOD score of 1.90).¹³ These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.¹¹⁸ No candidate genes have been identified.

A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of hereditary prostate cancer as well as one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a case revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.¹²⁰ This observation awaits confirmation.

¹ Ostrander EA, Stanford JL: Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet 67 (6): 1367-75, 2000.

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⁶⁶ Xu J, Zheng SL, Hawkins GA, et al.: Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. Am J Hum Genet 69 (2): 341-50, 2001.

⁶⁷ Xu J, Zheng SL, Komiya A, et al.: Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet 32 (2): 321-5, 2002.

⁶⁸ Xu J, Zheng SL, Komiya A, et al.: Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Am J Hum Genet 72 (1): 208-12, 2003.

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⁷² Sun J, Hsu FC, Turner AR, et al.: Meta-analysis of association of rare mutations and common sequence variants in the MSR1 gene and prostate cancer risk. Prostate 66 (7): 728-37, 2006.

⁷³ Hawkins GA, Mychaleckyj JC, Zheng SL, et al.: Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. Cancer Genet Cytogenet 137 (1): 1-7, 2002.

⁷⁴ Amundadottir LT, Sulem P, Gudmundsson J, et al.: A common variant associated with prostate cancer in European and African populations. Nat Genet 38 (6): 652-8, 2006.

⁷⁵ Freedman ML, Haiman CA, Patterson N, et al.: Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A 103 (38): 14068-73, 2006.

⁷⁶ Schumacher FR, Feigelson HS, Cox DG, et al.: A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res 67 (7): 2951-6, 2007.

⁷⁷ Suuriniemi M, Agalliu I, Schaid DJ, et al.: Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epidemiol Biomarkers Prev 16 (4): 809-14, 2007.

⁷⁸ Wang L, McDonnell SK, Slusser JP, et al.: Two common chromosome 8q24 variants are associated with increased risk for prostate cancer. Cancer Res 67 (7): 2944-50, 2007.

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⁸⁰ Gudmundsson J, Sulem P, Manolescu A, et al.: Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39 (5): 631-7, 2007.

⁸¹ Haiman CA, Patterson N, Freedman ML, et al.: Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39 (5): 638-44, 2007.

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⁸³ Liede A, Karlan BY, Narod SA: Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22 (4): 735-42, 2004.

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⁸⁶ Nastiuk KL, Mansukhani M, Terry MB, et al.: Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40 (3): 172-7, 1999.

⁸⁷ Vazina A, Baniel J, Yaacobi Y, et al.: The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Br J Cancer 83 (4): 463-6, 2000.

⁸⁸ Lehrer S, Fodor F, Stock RG, et al.: Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. Br J Cancer 78 (6): 771-3, 1998.

⁸⁹ Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.

⁹⁰ Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996.

⁹¹ Roa BB, Boyd AA, Volcik K, et al.: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14 (2): 185-7, 1996.

⁹² Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.

⁹³ Giusti RM, Rutter JL, Duray PH, et al.: A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40 (10): 787-92, 2003.

⁹⁴ Kirchhoff T, Kauff ND, Mitra N, et al.: BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 10 (9): 2918-21, 2004.

⁹⁵ Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003.

⁹⁶ Agalliu I, Kwon EM, Zadory D, et al.: Germline mutations in the BRCA2 gene and susceptibility to hereditary prostate cancer. Clin Cancer Res 13 (3): 839-43, 2007.

⁹⁷ Zuhlke KA, Madeoy JJ, Beebe-Dimmer J, et al.: Truncating BRCA1 mutations are uncommon in a cohort of hereditary prostate cancer families with evidence of linkage to 17q markers. Clin Cancer Res 10 (18 Pt 1): 5975-80, 2004.

⁹⁸ Narla G, Heath KE, Reeves HL, et al.: KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 294 (5551): 2563-6, 2001.

⁹⁹ Narla G, Difeo A, Reeves HL, et al.: A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 65 (4): 1213-22, 2005.

¹⁰⁰ Koivisto PA, Hyytinen ER, Matikainen M, et al.: Kruppel-like factor 6 germ-line mutations are infrequent in Finnish hereditary prostate cancer. J Urol 172 (2): 506-7, 2004.

¹⁰¹ Bar-Shira A, Matarasso N, Rosner S, et al.: Mutation screening and association study of the candidate prostate cancer susceptibility genes MSR1, PTEN, and KLF6. Prostate 66 (10): 1052-60, 2006.

¹⁰² Cybulski C, Górski B, Debniak T, et al.: NBS1 is a prostate cancer susceptibility gene. Cancer Res 64 (4): 1215-9, 2004.

¹⁰³ Swift M, Chase C: Cancer in families with xeroderma pigmentosum. J Natl Cancer Inst 62 (6): 1415-21, 1979.

¹⁰⁴ Geoffroy-Perez B, Janin N, Ossian K, et al.: Variation in breast cancer risk of heterozygotes for ataxia-telangiectasia according to environmental factors. Int J Cancer 99 (4): 619-23, 2002.

¹⁰⁵ Tamimi RM, Hankinson SE, Spiegelman D, et al.: Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study. Breast Cancer Res 6 (4): R416-22, 2004.

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¹¹¹ Brose MS, Rebbeck TR, Calzone KA, et al.: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94 (18): 1365-72, 2002.

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¹¹³ Rennert H, Zeigler-Johnson CM, Addya K, et al.: Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men. Cancer Epidemiol Biomarkers Prev 14 (4): 949-57, 2005.

¹¹⁴ Narla G, DiFeo A, Yao S, et al.: Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread. Cancer Res 65 (13): 5761-8, 2005.

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Polymorphisms and Prostate Cancer Susceptibility

While many research teams have collected multiplex prostate cancer families with the goal of identifying rare, highly penetrant prostate cancer genes , other investigators have studied the potential roles of more common genetic variants as modifiers of prostate cancer risk. While these polymorphisms may not be associated with a large increase in relative risk, these variants may have a high population attributable risk because they are common. For example, if the population attributable risk of prostate cancer associated with a genetic variant was 10% among carriers, that would imply that 10% of prostate cancer could be explained by the presence of this variant among carriers. For a rare variant, the proportion of cancer in the population attributed to the variant would be much less than 10%. Thus, a small increase in the relative risk of prostate cancer associated with a genetic variant that occurs frequently in the general population might, theoretically, account for a larger proportion of all prostate cancers than would the effects of a mutation in a rare gene, such as HPC1. This fact has provided much of the stimulus for studying the role of common genetic variants in the pathogenesis of prostate cancer and other cancers.

Androgen receptor gene variants have been examined in relation to both prostate cancer risk and disease progression. The androgen receptor is expressed during all stages of prostate carcinogenesis.¹ Altered activity of the androgen receptor due to inherited variants of the androgen receptor gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the androgen receptor gene (located on the X chromosome ) has been associated with the risk of prostate cancer.^2,3 Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.^{1,2,3,4,5,6,7,8,9,10,11,12} A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR] = 1.2; 95% confidence interval [CI], 1.1–1.3) and short GGN length (OR = 1.3; 95% CI, 1.1–1.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than 1, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.¹³ Subsequently, the large Multiethnic Cohort Study (MEC) of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR 1.02; P = .11) between CAG repeat size and prostate cancer.¹⁴ A study of 1,461 Swedish men with prostate cancer compared with 796 control men reported an association between AR alleles with greater than 22 CAG repeats and prostate cancer (OR = 1.35; 95% CI, 1.08–1.69; P = .03).^15,

Molecular epidemiology studies have also examined genetic polymorphisms of the 5-alpha-reductase Type II gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydroxytestosterone (DHT) by 5-alpha-reductase type II.¹⁶ Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.^17,18,

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.¹⁹ Ten alleles fall into 3 families that differ in the number of TA dinucleotide repeats.^16,20 Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.^1,16 A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, though a relationship could not be definitively excluded.²¹ This meta-analysis also examined the potential roles of 2 coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer compared with 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR = 1.45; 95% CI 1.01–2.08; OR = 1.49; 95% CI 1.03–2.15).^15,

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of single nucleotide polymorphisms (SNPs) in the estrogen receptor β (ERβ) gene and prostate cancer. One SNP in the promoter region of ERβ, rs2987983, was associated with an overall prostate cancer risk of 23% and a 35% risk for localized disease.²² This study awaits replication.

Molecular epidemiology studies of prostate cancer have also examined associations with vitamin D receptor genes ^23,24 and with single nucleotide polymorphism (SNP) variants in phase I and phase II genes such as CYP1A1, CYP2D6, CYP17A2, CYP3A4, GST, and NAT1 and NAT2, with inconsistent results.^25,

An association between genetic variants in apoptotic genes and prostate cancer risk has been proposed. The BCL-2 gene has antiapoptotic functions. A case-control study found a 70% decrease in prostate cancer risk in European Americans with the -938AA genotype in the BCL-2 gene and an approximate 60% decrease in risk in Jamaican men of African descent with the 21G allele. Further studies are needed to confirm these findings.^26,

Concerns have been raised that differences in ethnic composition (population stratification) may confound the results of some prostate cancer association studies because the incidence of prostate cancer varies according to ethnicity. If a polymorphism also exhibits different frequencies according to race, it may appear to be associated with the disease in the absence of a true causal relationship. This issue was explored in a study in which the CYP3A4-V allele appeared to be statistically associated with increased prostate cancer risk in African Americans (P = .007) and European Americans (P = .02), but not in Nigerians.²⁷ However, when the investigators added 10 markers at other chromosomal regions, the significance for CYP3A4-V in African American men was lost. When the P value above was corrected for the observed population stratification, it was no longer significant. Thus, population admixture and stratification can create false associations (and obscure true associations) between genetic polymorphisms and disease risk. Family-based association methods can also be used to minimize confounding by population stratification. An association has been identified between a single polymorphism in the CYP17 gene and prostate cancer using a set of 461 discordant sibling pairs.²⁸ Since the siblings are genetically related, population stratification cannot bias this finding. A study of 1,461 Swedish men with prostate cancer compared with 796 control men reported an inverse association between a CYP17 variant and prostate cancer risk (P = .04).^15,

In addition to the specific examples cited above, there have been additional candidate genes examined for their potential roles in genetic susceptibility to prostate cancer. These include both systematic literature reviews ^25,29,30 and formal meta-analyses evaluating specific candidate genes ^31,32 on this complicated and evolving subject. Due to the cross-sectional nature of these studies, as well as the inconsistent results among reports targeting the same gene, these findings currently have no role in clinical decision making. The results of large, adequately powered, prospective analyses of these associations will be required.

In an effort to more comprehensively evaluate the relationship between genetic variants in a particular gene and the risk of a specific cancer, single SNP association studies are augmented by a haplotype -based analytical strategy, in which a series of closely linked SNPs is selected to represent the entire gene. The MEC investigators provide a recent example of this approach as it applies to prostate cancer.³³ Twenty-nine SNPs were used to define 4 haplotypes spanning the IGF1 gene. The investigators observed modest statistically significant elevations in relative risk (ranging from 1.19–1.25) for each of the 4 haplotypes. They concluded that inherited variation in IGF1 may play a role in the risk of prostate cancer.

¹ Ruijter E, van de Kaa C, Miller G, et al.: Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 20 (1): 22-45, 1999.

² Giovannucci E, Stampfer MJ, Krithivas K, et al.: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A 94 (7): 3320-3, 1997.

³ Stanford JL, Just JJ, Gibbs M, et al.: Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 57 (6): 1194-8, 1997.

⁴ Ekman P: Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Eur Urol 35 (5-6): 362-9, 1999.

⁵ Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22 (15): 3181-6, 1994.

⁶ Platz EA, Giovannucci E, Dahl DM, et al.: The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 7 (5): 379-84, 1998.

⁷ Bratt O, Borg A, Kristoffersson U, et al.: CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk. Br J Cancer 81 (4): 672-6, 1999.

⁸ Ekman P, Grönberg H, Matsuyama H, et al.: Links between genetic and environmental factors and prostate cancer risk. Prostate 39 (4): 262-8, 1999.

⁹ Lange EM, Chen H, Brierley K, et al.: The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer. Cancer Epidemiol Biomarkers Prev 9 (4): 439-42, 2000.

¹⁰ Edwards SM, Badzioch MD, Minter R, et al.: Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. Int J Cancer 84 (5): 458-65, 1999.

¹¹ Correa-Cerro L, Wöhr G, Häussler J, et al.: (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population. Eur J Hum Genet 7 (3): 357-62, 1999.

¹² Mononen N, Ikonen T, Autio V, et al.: Androgen receptor CAG polymorphism and prostate cancer risk. Hum Genet 111 (2): 166-71, 2002.

¹³ Zeegers MP, Kiemeney LA, Nieder AM, et al.: How strong is the association between CAG and GGN repeat length polymorphisms in the androgen receptor gene and prostate cancer risk? Cancer Epidemiol Biomarkers Prev 13 (11 Pt 1): 1765-71, 2004.

¹⁴ Freedman ML, Pearce CL, Penney KL, et al.: Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study. Am J Hum Genet 76 (1): 82-90, 2005.

¹⁵ Lindström S, Zheng SL, Wiklund F, et al.: Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway. Prostate 66 (16): 1729-43, 2006.

¹⁶ Reichardt JK, Makridakis N, Henderson BE, et al.: Genetic variability of the human SRD5A2 gene: implications for prostate cancer risk. Cancer Res 55 (18): 3973-5, 1995.

¹⁷ Brawley OW, Ford LG, Thompson I, et al.: 5-Alpha-reductase inhibition and prostate cancer prevention. Cancer Epidemiol Biomarkers Prev 3 (2): 177-82, 1994.

¹⁸ Ross RK, Bernstein L, Lobo RA, et al.: 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339 (8798): 887-9, 1992.

¹⁹ Davis DL, Russell DW: Unusual length polymorphism in human steroid 5 alpha-reductase type 2 gene (SRD5A2). Hum Mol Genet 2 (6): 820, 1993.

²⁰ Kantoff PW, Febbo PG, Giovannucci E, et al.: A polymorphism of the 5 alpha-reductase gene and its association with prostate cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev 6 (3): 189-92, 1997.

²¹ Ntais C, Polycarpou A, Ioannidis JP: SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 12 (7): 618-24, 2003.

²² Thellenberg-Karlsson C, Lindström S, Malmer B, et al.: Estrogen receptor beta polymorphism is associated with prostate cancer risk. Clin Cancer Res 12 (6): 1936-41, 2006.

²³ Taylor JA, Hirvonen A, Watson M, et al.: Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res 56 (18): 4108-10, 1996.

²⁴ Ingles SA, Ross RK, Yu MC, et al.: Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 89 (2): 166-70, 1997.

²⁵ Coughlin SS, Hall IJ: A review of genetic polymorphisms and prostate cancer risk. Ann Epidemiol 12 (3): 182-96, 2002.

²⁶ Kidd LR, Coulibaly A, Templeton TM, et al.: Germline BCL-2 sequence variants and inherited predisposition to prostate cancer. Prostate Cancer Prostatic Dis 9 (3): 284-92, 2006.

²⁷ Kittles RA, Chen W, Panguluri RK, et al.: CYP3A4-V and prostate cancer in African Americans: causal or confounding association because of population stratification? Hum Genet 110 (6): 553-60, 2002.

²⁸ Douglas JA, Zuhlke KA, Beebe-Dimmer J, et al.: Identifying susceptibility genes for prostate cancer--a family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-beta. Cancer Epidemiol Biomarkers Prev 14 (8): 2035-9, 2005.

²⁹ Rebbeck TR: Inherited genotype and prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev 11 (10 Pt 1): 945-52, 2002.

³⁰ Gsur A, Feik E, Madersbacher S: Genetic polymorphisms and prostate cancer risk. World J Urol 21 (6): 414-23, 2004.

³¹ Ntais C, Polycarpou A, Ioannidis JP: Vitamin D receptor gene polymorphisms and risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 12 (12): 1395-402, 2003.

³² Ntais C, Polycarpou A, Ioannidis JP: Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 14 (1): 176-81, 2005.

³³ Cheng I, Stram DO, Penney KL, et al.: Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. J Natl Cancer Inst 98 (2): 123-34, 2006.

Interventions in Familial Prostate Cancer

Refer to the PDQ summaries on Screening for Prostate Cancer; Prevention of Prostate Cancer; and Prostate Cancer Treatment for more information on interventions for sporadic nonfamilial forms of prostate cancer.

As with any disease process, decisions about risk-reducing interventions for patients with an inherited predisposition to prostate cancer are best guided by randomized controlled clinical trials, and by knowledge of the underlying natural history of the process. Unfortunately, little is known about either the natural history or the inherent biologic aggressiveness of familial prostate cancer compared with sporadic forms. Existing studies of the natural history of prostate cancer in men with a positive family history are predominantly based on retrospective case series. Because awareness of a positive family history can lead to more frequent work-ups for cancer and result in apparently earlier prostate cancer detection, assessments of disease progression rates and survival after diagnosis are subject to selection, lead time, and length biases. Refer to the PDQ summary on Cancer Screening Overview for more information.

Given the paucity of information on the natural history of prostate cancer in men with a hereditary predisposition, decisions about risk reduction, early detection, and therapy are currently based on the literature used to guide interventions in sporadic prostate cancer, coupled with the best clinical judgment of those responsible for the care of these patients, with the active participation of well-informed high-risk patients.

Primary Prevention

There are no definitive studies of primary prevention strategies in men with a hereditary risk of prostate cancer. Thus, there are no definitive recommendations that can be offered to these patients to reduce their risk for prostate cancer at the present time.

The recently published Prostate Cancer Prevention Trial (PCPT), a prospective, randomized clinical trial of finasteride versus placebo, demonstrated a 25% reduction in prostate cancer risk among study participants receiving finasteride.¹ Finasteride administration produced statistically similar reductions in prostate cancer risk in family-history–positive (19% decrease) and family-history–negative (26% decrease) subjects. A subsequent PCPT publication suggested that end-of-study biopsies in asymptomatic men with serum prostate-specific antigen (PSA) values consistently lower than 4.0 ng/mL were more likely to detect prostate cancer in men with an affected first-degree relative (19.7%) versus those with a negative family history (14.4%).^1,

Level of Evidence: Iaii

Refer to the PDQ summary on Prevention of Prostate Cancer for a more detailed description of the prevention of prostate cancer in the general population. Information about ongoing prostate cancer prevention clinical trials is available from the NCI Web site.

Screening

There is little information about the net benefits and harms of screening men at higher risk of prostate cancer. There is no evidence to support specific screening approaches in prostate cancer families at high risk. Risks and benefits of routine screening in the general population are discussed in the PDQ summary on Screening for Prostate Cancer.

There is limited information about the efficacy of commonly available screening tests such as the digital rectal examination (DRE) or serum PSA in men genetically predisposed to developing prostate cancer. Furthermore, comparing the results of studies examining the efficacy of screening for prostate cancer is difficult; studies vary with regard to the cut-off values chosen for an elevated PSA test. For a given sensitivity and specificity of a screening test, the positive predictive value (PPV [proportion of men with positive tests who have prostate cancer]) increases as the underlying prevalence of disease rises. Therefore, it is theoretically possible that the PPV and diagnostic yield will be higher for the DRE and for PSA in men with a genetic predisposition than in average-risk populations.^2,3,

Currently, there are only a few case-control studies and no published randomized trials examining screening in men with an increased risk of prostate cancer. A 10-year longitudinal study of serum PSA and DRE every 6 to 12 months in high-risk men aged 40 years and older has been conducted.⁴ Two high-risk categories (1,227 men with a family history of prostate cancer and 1,224 African American men) were compared with 15,964 low-risk non–African American men without a family history of prostate cancer. Suspicious screening results were present in 7% of non–African American men with a family history of prostate cancer, 8% of the low-risk African American men, and 20% of African American men with a family history of prostate cancer. The PPV was inversely proportional to age for those who had an abnormal screening test and underwent biopsy. Among men aged 40 to 49 years, the PPV was 50% for non–African American men with a positive family history, 54% for African American men without a family history, and 75% among African American men with a family history, compared with 38%, 49%, and 52%, respectively, among men aged 50 years and older. Of the 16 cancers detected in high-risk men younger than 50 years, 15 were clinically significant, with intermediate Gleason scores (5–7), and 3 were not confined to the prostate.^4,

One screening study of the relatives of 435 men with prostate cancer measured serum PSA every 12 months for 2 years. Four hundred and forty-two participants were classified into 2 groups: sporadic, defined as only one first-degree relative with prostate cancer; or familial, with 2 or more cases of prostate cancer. PSA higher than 4 ng/mL was present in 0.8% in men aged 40 to 49 years, compared with 12.4% of men older than 50 years. No differences in prostate cancer detection rates or elevated PSA levels were found between sporadic and familial groups. Of the 10 prostate cancers detected in this study, 9 were clinically localized and of intermediate Gleason scores (5–7).^5,

In a Finnish prostate cancer screening study, family history of prostate cancer was obtained in 2,099 prostate cancer patients.³ This resulted in the identification of 103 prostate cancer families with 2 or more affected first- or second-degree relatives having at least one living first-degree unaffected male. From those families, 209 of 226 eligible first-degree unaffected asymptomatic males aged 45 to 75 years were enrolled in a study involving a single serum PSA measurement. An elevated PSA (2.6–28.3 mg/L) was identified in 21 (10%) of subjects. Subsequent biopsies revealed prostate adenocarcinoma in 7 (3.3%), including one at an advanced stage, and prostatic intraepithelial neoplasia in 2 (1%). The mean age of PSA-detected cancers was 65.1 years, 7 years younger than the average age of prostate cancer diagnosis in Finland. In men with a family history of early-onset prostate cancer (mean age of diagnosis in the family, < 60 years), the frequency of elevated PSAs was 28.6% and subclinical prostate cancer was 14.3%, significantly higher than the 2.3% to 4.5% reported in other PSA screening studies of this type.^{6,7,8,9,10,11} These findings, however, may not be comparable to US studies: prostate screening practices may differ between Finland and the United States, and rates of prior screening in the population studied were not reported.

A large French Canadian study reported findings from 6,390 men older than 45 years who underwent prostate screening consisting of annual serum PSA and DRE followed by transrectal ultrasound imaging if an abnormality was detected. Of these, 1,563 (24.5%) were found to have an abnormal rectal exam (n = 504) or a PSA > 3.0 μg/L (n = 1,261).¹¹ Twenty-six refused follow-up; of the remaining subjects, 50.5% underwent biopsy following ultrasound examination. Prostate cancer was identified in 264 men, representing 34.0% of those who underwent biopsy and 4.1% of all 6,390 enrolled subjects. The prevalence of screen-detected prostate cancer was highest in men reporting a brother with prostate cancer (10.21%), as opposed to those reporting a father with prostate cancer (4.75%). Overall, in this study, the PPV of a PSA more than 3.0 μg/L was significantly associated with a family history. The PPV was 28.6% in men with a prostate cancer family history and 17.9% in men without an affected first-degree relative. The increase in PPV of PSA was confined to the men with a normal rectal exam.^11,

A PSA screening study of 20,716 asymptomatic men identified by the Finnish population-based registry did not find a higher PPV for men with a family history of one or more first-degree relatives with prostate cancer, compared with controls. Using a PSA cut-off of 4.0 ng/mL, the PPV of an abnormal PSA for the 964 men with a positive family history was 28% versus 31% for the 19,347 men without a family history. The relative risk (RR) of developing prostate cancer among male relatives of men with prostate cancer was modest (RR = 1.3; 95% confidence interval [CI], 0.95–1.71), suggesting that the family history was not a significant prostate cancer risk factor in this study. This unexpected finding might account for the lack of differences seen in the PPV of the PSA test when comparing men with and without a family history of prostate cancer.^12,

An analysis of data from the control arm of the PCPT yielded a prostate cancer risk model that incorporated PSA level, family history of prostate cancer, and DRE results to predict the likelihood that a man undergoing biopsy would have prostate cancer. Men younger than 55 years were not eligible for participation in this study; therefore, the usefulness of this model in the management of young men from prostate cancer families is unknown.^13,

Current recommendations for screening at-risk members of familial or hereditary prostate cancer kindreds are based on expert opinion panels.^14,15 Therefore, the overall summary of evidence related to the efficacy of screening is level 5. There are no randomized studies that address screening at-risk members of familial or hereditary prostate cancer kindreds, and the observational data are contradictory. Refer to the Screening Behaviors section of this summary for more information on factors that influence prostate cancer screening.

Level of Evidence: 5

Treatment

Various studies have shown better, worse, or similar survival rates after treatment in men with prostate cancer who have a family history of affected first-degree relatives, compared with those who have a negative family history.^16,17,18,19 There is extensive literature addressing whether family history of prostate cancer is linked with aggressive tumor behavior and consequently a worse prognosis. The most current longitudinal report suggests that this is not likely the case.^20,

In general, there is insufficient information available to determine whether treatment strategies differ in efficacy for sporadic cases versus familial cases of prostate cancer. Decisions about treating familial cases of cancer are currently guided by information derived from therapeutic studies in the general population of prostate cancer patients. Therefore, no level of evidence is assigned. A detailed discussion of treatment in these patients is found in the PDQ Prostate Cancer treatment summary, and information about ongoing prostate cancer treatment clinical trials is available from the NCI Web site.

Level of Evidence: Not assigned

¹ Thompson IM, Goodman PJ, Tangen CM, et al.: The influence of finasteride on the development of prostate cancer. N Engl J Med 349 (3): 215-24, 2003.

² Sartor O: Early detection of prostate cancer in African-American men with an increased familial risk of disease. J La State Med Soc 148 (4): 179-85, 1996.

³ Matikainen MP, Schleutker J, Mörsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 5 (6): 1275-9, 1999.

⁴ Catalona WJ, Antenor JA, Roehl KA, et al.: Screening for prostate cancer in high risk populations. J Urol 168 (5): 1980-3; discussion 1983-4, 2002.

⁵ Valeri A, Cormier L, Moineau MP, et al.: Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives. J Urol 168 (2): 483-7, 2002.

⁶ Auvinen A, Tammela T, Stenman UH, et al.: Screening for prostate cancer using serum prostate-specific antigen: a randomised, population-based pilot study in Finland. Br J Cancer 74 (4): 568-72, 1996.

⁷ Labrie F, Dupont A, Suburu R, et al.: Serum prostate specific antigen as pre-screening test for prostate cancer. J Urol 147 (3 Pt 2): 846-51; discussion 851-2, 1992.

⁸ Standaert B, Denis L: The European Randomized Study of Screening for Prostate Cancer: an update. Cancer 80 (9): 1830-4, 1997.

⁹ Catalona WJ, Smith DS, Ratliff TL, et al.: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 270 (8): 948-54, 1993.

¹⁰ Mettlin C, Murphy GP, Babaian RJ, et al.: The results of a five-year early prostate cancer detection intervention. Investigators of the American Cancer Society National Prostate Cancer Detection Project. Cancer 77 (1): 150-9, 1996.

¹¹ Narod SA, Dupont A, Cusan L, et al.: The impact of family history on early detection of prostate cancer. Nat Med 1 (2): 99-101, 1995.

¹² Mäkinen T, Tammela TL, Stenman UH, et al.: Family history and prostate cancer screening with prostate-specific antigen. J Clin Oncol 20 (11): 2658-63, 2002.

¹³ Thompson IM, Ankerst DP, Chi C, et al.: Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 98 (8): 529-34, 2006.

¹⁴ Scardino P: Update: NCCN prostate cancer Clinical Practice Guidelines. J Natl Compr Canc Netw 3 (Suppl 1): S29-33, 2005.

¹⁵ National Comprehensive Cancer Network.: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 1.2006. National Comprehensive Cancer Network, 2006. Available online. Last accessed March 5, 2007.

¹⁶ Bauer JJ, Srivastava S, Connelly RR, et al.: Significance of familial history of prostate cancer to traditional prognostic variables, genetic biomarkers, and recurrence after radical prostatectomy. Urology 51 (6): 970-6, 1998.

¹⁷ Bova GS, Partin AW, Isaacs SD, et al.: Biological aggressiveness of hereditary prostate cancer: long-term evaluation following radical prostatectomy. J Urol 160 (3 Pt 1): 660-3, 1998.

¹⁸ Spangler E, Zeigler-Johnson CM, Malkowicz SB, et al.: Association of prostate cancer family history with histopathological and clinical characteristics of prostate tumors. Int J Cancer 113 (3): 471-4, 2005.

¹⁹ Kupelian PA, Kupelian VA, Witte JS, et al.: Family history of prostate cancer in patients with localized prostate cancer: an independent predictor of treatment outcome. J Clin Oncol 15 (4): 1478-80, 1997.

²⁰ Kupelian PA, Reddy CA, Reuther AM, et al.: Aggressiveness of familial prostate cancer. J Clin Oncol 24 (21): 3445-50, 2006.

Prostate Cancer Risk Assessment

The purpose of this section is to describe current approaches to assessing and counseling patients about susceptibility to prostate cancer. Genetic counseling for men at increased risk of prostate cancer encompasses all of the elements of genetic counseling for other hereditary cancers. (Refer to the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling for more information.) The components of genetic counseling include concepts of risk for prostate cancer, reinforcing the importance of detailed family history , pedigree analysis to derive age-related risk, and offering participation in research studies to those individuals who have multiple affected family members.^1,2 Genetic testing for prostate cancer susceptibility is not available outside of the context of a research study. Families with prostate cancer can be referred to ongoing research studies; however, these studies will not provide individual genetic results to participants.

Prostate cancer will affect an estimated 1 in 6 American men over their lifetime. Currently, evidence exists to support the hypothesis that approximately 5% to 10% of all prostate cancer is due to rare autosomal dominant prostate cancer susceptibility genes .^3,4 The proportion of prostate cancer associated with an inherited susceptibility may be even larger.^5,6,7 Men are generally considered to be candidates for genetic counseling regarding prostate cancer risk if they have a family history of prostate cancer. The Hopkins Criteria provide a working definition of hereditary prostate cancer families.⁸ The 3 criteria include:

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 one of these criteria to be considered to have hereditary prostate cancer. One study investigated attitudes regarding prostate cancer susceptibility among sons of men with prostate cancer.⁹ They found that 90% of sons were interested in knowing if there is an inherited susceptibility to prostate cancer and would be likely to undergo screening as well as consider genetic testing if there was a family history of prostate cancer; however, similar high levels of interest in genetic testing for other hereditary cancer syndromes have not generally been borne out in testing uptake once the clinical genetic test becomes available.

Risk Assessment and Analysis

Assessment of a man concerned about his inherited risk of prostate cancer should include taking a detailed family history, eliciting information regarding personal prostate cancer risk factors, documenting other medical problems, and evaluating genetics-related psychosocial issues.

Family history documentation is based on construction of a pedigree, and generally includes:

• The history of cancer in both maternal and paternal bloodlines
• All primary cancer diagnoses (not just prostate cancer) and ages at onset
• Race and ethnicity
• Other health problems including benign prostatic hypertrophy^10,

(Refer to the Taking a Family History section in the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling for a more detailed description of taking a family history.)

Analysis of the family history generally consists of 4 components:

1. Evaluation of the pattern of cancers in the family to identify cancer clusters, which might suggest a known inherited cancer syndrome. In addition to site-specific prostate cancer, other cancer susceptibility syndromes include prostate cancer as a component tumor (e.g., Hereditary Breast/Ovarian Cancer Syndrome [associated with mutations in BRCA1 and BRCA2]).
2. Assessment for genetic transmission. The pedigree should be assessed for evidence of both autosomal dominant and X-linked inheritance , which may be associated with a higher likelihood of an inherited susceptibility to prostate cancer. Autosomal dominant transmission is characterized by the presence of affected family members in sequential generations, with approximately 50% of males in each generation affected with prostate cancer. X-linked inheritance is suggested by apparent transmission of susceptibility from affected males in the maternal lineage. Refer to the Analysis of the Family History section in the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling for more information.
3. Age at onset of prostate cancer in family. An inherited susceptibility to prostate cancer may be likely in families with early-onset (inconsistently defined) prostate cancer.¹¹ However, genetic research is also underway in families with an older age of prostate cancer onset. In the aggregate, the data are inconsistent relative to whether hereditary prostate cancer is routinely characterized by a younger-than-usual age at diagnosis.
4. Risk assessment based on family and epidemiological studies. Multiple studies have reported that first-degree relatives of men affected with prostate cancer are 2 to 3 times more likely to develop prostate cancer than are men in the general population. In some studies, the relative risk of prostate cancer is highest among families who develop prostate cancer at an early age, consistent with other cancer susceptibility syndromes where early age at onset is a common feature. It has been estimated that male relatives of men diagnosed with prostate cancer younger than 53 years have a 40% lifetime cumulative risk of developing prostate cancer.¹² A population-based case-control study of more than 1,500 cases and 1,600 controls, in which Caucasians, African Americans, and Asian Americans were studied, reported an odds ratio of 2.5 for men with an affected first-degree relative after adjusting for age and ethnicity.¹³ For men with a brother and father or son affected with prostate cancer, the relative risk was estimated to be 6.4.

A number of studies have examined the accuracy of the family history of prostate cancer provided by men with prostate cancer. This has clinical importance when risk assessments are based on unverified family history information. In an Australian study of 154 unaffected men with a family history of prostate cancer, self-reported family history was verified from cancer registry data in 89.6% of cases.¹⁴ Accuracy of age at diagnosis within a 3-year range was correct in 83% of the cases, and accuracy of age at diagnosis within a 5-year range was correct in 93% of the cases. Self-reported family history from men younger than 55 years and reports about first-degree relatives had the highest degree of accuracy.¹⁴ Self-reported family history of prostate cancer, however, may not be reliably reported over time,¹⁵ which underscores the need to verify objectively reported prostate cancer diagnoses when trying to determine whether a patient has a significant family history.

The personal health and risk-factor history includes, but is not limited to:

• Family history
• Age
• Race
• Current and past diet history, including fat intake
• Current and past use of drugs that can affect prostatic growth, such as steroids (e.g., finasteride [Proscar])
• Current and past use of complementary and alternative medications (e.g., saw palmetto, PC-SPES)¹⁶ (For more information on PC-SPES, refer to the PDQ complementary and alternative medicine summary on PC-SPES.)

The most definitive risk factors for prostate cancer are age, race, and family history.¹⁷ The correlation between other risk factors and prostate cancer risk is not clearly established. Despite this limitation, cancer risk counseling is an educational process that provides details regarding the state of the knowledge of prostate cancer risk factors. The discussion regarding these other risk factors should be individualized to incorporate the consultand ’s personal health and risk factor history. (For a more detailed description of prostate cancer risk factors, refer to the Risk Factors for Prostate Cancer section of this summary.)

The psychosocial assessment in this context might include evaluation of:

• Level of psychological distress
• Perceived risk of prostate cancer
• Past history of depression, anxiety, or other mental illness

One study found that psychological distress was greater among men attending prostate cancer screening who had a family history of the disease, particularly if they also reported an overestimation of prostate cancer risk. Psychological distress and elevated risk perception may influence adherence to cancer screening and risk management strategies. Consultation with a mental health professional may be valuable if serious psychosocial issues are identified.^18,

Genetic Testing

At this time, clinical genetic testing to detect inherited prostate cancer predisposition is not available. None of the candidate susceptibility genes have been unequivocally associated with prostate cancer predisposition. (Refer to the Prostate Cancer Susceptibility Loci section of this summary for more information.) For families suspected of having an inherited susceptibility to prostate cancer, participation in ongoing research studies investigating the genetic basis of inherited prostate cancer susceptibility can be considered.

¹ Nieder AM, Taneja SS, Zeegers MP, et al.: Genetic counseling for prostate cancer risk. Clin Genet 63 (3): 169-76, 2003.

² Bruner DW, Baffoe-Bonnie A, Miller S, et al.: Prostate cancer risk assessment program. A model for the early detection of prostate cancer. Oncology (Huntingt) 13 (3): 325-34; discussion 337-9, 343-4 pas, 1999.

³ Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990.

⁴ Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992.

⁵ Lesko SM, Rosenberg L, Shapiro S: Family history and prostate cancer risk. Am J Epidemiol 144 (11): 1041-7, 1996.

⁶ 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.

⁷ 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.

⁸ Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993.

⁹ Bratt O, Kristoffersson U, Lundgren R, et al.: Sons of men with prostate cancer: their attitudes regarding possible inheritance of prostate cancer, screening, and genetic testing. Urology 50 (3): 360-5, 1997.

¹⁰ Pienta KJ, Esper PS: Risk factors for prostate cancer. Ann Intern Med 118 (10): 793-803, 1993.

¹¹ Giovannucci E: How is individual risk for prostate cancer assessed? Hematol Oncol Clin North Am 10 (3): 537-48, 1996.

¹² Neuhausen SL, Skolnick MH, Cannon-Albright L: Familial prostate cancer studies in Utah. Br J Urol 79 (Suppl 1): 15-20, 1997.

¹³ Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995.

¹⁴ Gaff CL, Aragona C, MacInnis RJ, et al.: Accuracy and completeness in reporting family history of prostate cancer by unaffected men. Urology 63 (6): 1111-6, 2004.

¹⁵ Weinrich SP, Faison-Smith L, Hudson-Priest J, et al.: Stability of self-reported family history of prostate cancer among African American men. J Nurs Meas 10 (1): 39-46, 2002 Spring-Summer.

¹⁶ Barqawi A, Gamito E, O'Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004.

¹⁷ Stanford JL, Stephenson RA, Coyle LM, et al., eds.: Prostate Cancer Trends 1973-1995. Bethesda, Md: National Cancer Institute, 1999. NIH Pub. No. 99-4543. Also available online. Last accessed March 5, 2007.

¹⁸ Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999.

Psychosocial Issues in Prostate Cancer

Introduction

Research to date has included survey, focus group, and correlation studies on psychosocial issues related to prostate cancer risk. (Refer to the PDQ summary on Elements of Cancer Genetics Risk Assessment and Counseling for further information on psychological issues related to genetic counseling for cancer risk assessment .) Genetic testing for prostate cancer susceptibility genes , when testing becomes available, has the potential to identify those at highest risk, which facilitates risk-reducing interventions and early detection of prostate cancer. Having an understanding of the motivations of men who may consider genetic testing for inherited susceptibility to prostate cancer will help clinicians and researchers anticipate interest in testing. Further, these data will inform the nature and content of counseling strategies for men and their families, including consideration of the risks, benefits, decision-making issues, and informed consent for genetic testing.

Risk Perception

Knowledge about risk for prostate cancer is thought to be a factor influencing men’s decisions to pursue prostate cancer screening and possibly testing.¹ An emerging body of literature is now exploring risk perception for prostate cancer among men with and without a family history . Table 4 provides a summary of studies examining prostate cancer risk perception.

Table 4. Summary of Cross-Sectional Studies of Prostate Cancer Risk Perception

Study PopulationSample SizeProportion of Study Population That Accurately Reported Their Risk Other FindingsUnaffected men with a family history of prostate cancer ^2,120 men aged 40 to 72 years40%First-degree male relatives (FDR ) of men with prostate cancer ^3,105 men aged 40 to 70 years62%Men with brothers affected with prostate cancer ^4,111 men aged 33 to 78 yearsNot available38% of men reported their risk of prostate cancer to be the same or less than the average man.FDR of men with prostate cancer and a community sample ^5,56 men with a FDR with prostate cancer and 100 men without a FDR with prostate cancer all older than 40 years57%29% of men with a FDR thought that they were at the same risk as the average man, and 14% believed that they were at somewhat lower risk than average.

Study conclusions vary regarding whether first-degree relatives of prostate cancer patients accurately estimate their prostate cancer risk. Some studies found that men with a family history of prostate cancer considered their risk to be the same or less than that of the average man.^4,5 Other factors, including being married, have been associated with higher prostate cancer risk perception.⁶ A confounder in prostate cancer risk perception was confusion between benign prostatic hyperplasia and prostate cancer.^2,

Anticipated Interest in Genetic Testing

A number of studies summarized in Table 5 have examined participants' interest in genetic testing, if such a test were available for clinical use. Factors found to positively influence the interest in genetic testing include:

• Advice of their primary care physician⁷
• Combination of emotional distress and concern about prostate cancer treatment effects^8,
• Men with children^9,

Findings from these studies were not consistent regarding the influence of race, education, marital status, employment status, family history, and age on interest in genetic testing. The men studied expressed concerns about confidentiality of test results among employers, insurers, and family, as well as stigmatization, potential loss of insurability, and the cost of the test.⁷ These concerns are similar to those that have been reported in women contemplating genetic testing for breast cancer predisposition.^{10,11,12,13,14,15} Concerns voiced about testing positive for a mutation in a prostate cancer susceptibility gene included decreased quality of life secondary to interference with sex life in the event of a cancer diagnosis, increased anxiety, and elevated stress.^7,

Table 5. Summary of Cross-Sectional Studies of Anticipated Interest in Prostate Cancer Susceptibility Genetic Testing

Study PopulationSample SizePercent Expressing Interest in Genetic TestingOther FindingsProstate screening clinic participants ^16,342 men aged 40 to 97 years89%28% did not demonstrate an understanding of the concept of inherited predisposition to cancer General population; 9% with positive family history ^7,12 focus groups with a total of 90 men aged 18 to 70 yearsAll focus groupsAfrican American men ^17,320 men aged 21 to 98 years87%Most participants could not distinguish between genetic susceptibility testing and a prostate-specific antigen (PSA) blood testMen with and without first-degree male relatives with prostate cancer ^8,126 men over the age of 40; mean age 52.6 years 24% definitely; 50% probably Swedish men with a FDR with prostate cancer ^2,110 men aged 40 to 72 years76% definitely; 18% probably89% definitely or probably wanted their sons to undergo genetic testingSons of Swedish men with prostate cancer ^9,101 men aged 21 to 65 years90%; 100% of sons with 2 to 3 family members affected with prostate cancer60% expressed worry about having an increased risk for prostate cancerHealthy outpatient males with no history of prostate cancer ^18,400 men aged 40 to 69 years82%Healthy African American males with no history of prostate cancer ^19,413 African American men aged 40 to 70 years87%Belief in the efficacy of and intention to undergo prostate cancer screening was associated with testing interest

Overall, these reports and a study that developed a conceptual model to look at factors associated with intention to undergo genetic testing ²⁰ have shown a significant interest in genetic testing for prostate cancer susceptibility despite concerns about confidentiality and potential discrimination. These findings must be interpreted cautiously in predicting actual prostate cancer genetic test uptake once testing is available. In both Huntington disease and hereditary breast and ovarian cancers, hypothetical interest before testing was possible was much higher than actual uptake following availability of the test.^21,22,

Hereditary Prostate Cancer Families and Screening

The proportion of prostate cancers attributed to hereditary causes is estimated to be 5% to 10%,²³ and the risk for prostate cancer increases with the number of blood relatives with prostate cancer and young age at onset of prostate cancer within families.²⁴ There is considerable controversy in prostate cancer about the use of serum prostate-specific antigen ( PSA) measurement and digital rectal exam (DRE) for prostate cancer early detection in the general population, with different organizations suggesting significantly different screening algorithms and age recommendations. (Refer to the PDQ summary on Prostate Cancer treatment for more information on prostate cancer in the general population, and the Interventions section of this summary for more information on inherited prostate cancer susceptibility.) This variation is likely to add to patient and provider confusion about recommendations for screening by members of hereditary cancer families or first-degree relatives of prostate cancer patients. Psychosocial questions of interest include what individuals at increased risk understand about hereditary risk, whether informational interventions are associated with increased uptake of prostate cancer screening behaviors, and what the associated quality-of-life implications of screening are for individuals at increased risk. Also of interest is the role of the primary care provider in helping those at increased risk identify their risk and undergo age- and family-history–appropriate screening. The literature on psychosocial aspects of hereditary prostate cancer is quite limited, but there are implications from even the small number of current studies for primary care practice.

Screening behaviors

In most cancers, the goal of improved knowledge of hereditary risk can be translated rather easily into a desired increase in adherence to approved and recommended (if not proven) screening behaviors. This is complicated for prostate cancer screening by the lack of clear recommendations for men in both high-risk and general populations. (Refer to the Screening section of this summary for more information.) In addition, controversy exists with regard to the value of early diagnosis of prostate cancer. This creates uncertainty for patients and providers and challenges the psychosocial factors related to screening behavior.

Several small studies have examined the behavioral correlates of prostate cancer screening at average and increased prostate cancer risk based on family history; these are summarized in Table 6. In general, results appear contradictory whether men with a family history are more likely to be screened than those not at risk, and whether the screening is appropriate for their risk status. Furthermore, most of the studies had relatively small numbers of subjects, and the criteria for screening were not uniform, making generalization difficult.

Table 6. Summary of Studies of Behavioral Correlates for Prostate Cancer Screening

Study PopulationSample SizePercent Undergoing ScreeningPredictive Correlates for Screening BehaviorDRE = digital rectal exam; NHIS = National Health Interview Survey; PSA = prostate-specific antigen; U.S. = United States.Unaffected men with at least one first-degree relative with prostate cancer.^25,82 men (aged ≥40 years; mean age 50.5 years).PSA Aged >50 years .50% reported PSA screening within the previous 14 months.Annual income ≥U.S. $40,000.History of PSA screening prior to study enrollment.Higher levels of self-efficacy and response efficacy for undergoing prostate cancer screening.Sons of men with prostate cancer.^26,124 men (60 men with a history of prostate cancer aged 38–84 years, median age 59 years; 64 unaffected men aged 31–78 years, median age 55 years).PSA 39.4% patient request.Unaffected men: 95.3% reported ever having a PSA. 35.6% physician request.Affected men: 71.7% reported ever having a PSA prior to diagnosis. DRE Unaffected men: 96.9% reported ever having a DRE.Affected men: 91.5% reported ever having a DRE prior to diagnosis. Both PSA and DRE Unaffected men: 93.8% had both. Affected men: 70.0% reported having both prior to diagnosis. Unaffected men with and without a first-degree relative with prostate cancer.^5,156 men aged ≥40 years (56 men with a first-degree relative; 100 men without a first-degree relative).PSA Older age. 63% reported ever having a PSA.First-degree relatives reported higher disease vulnerability and less belief in disease prevention, but this did not result in increased prostate cancer screening when compared to those without a first-degree relative.DRE 86% reported ever having a DRE.Unaffected Swedish men from families with a 50% probability of carrying a mutation in a dominant prostate cancer susceptibility gene.^2,110 men aged 50–72 years. 68% of men ≥50 years were screened for prostate cancer.Greater number of relatives with prostate cancer. Low score on the avoidance subscales of the Impact of Event Scale.^27,Brothers or sons of men with prostate cancer.^28,136 men aged 40–70 years (72% were African American men).PSA Greater number of relatives with prostate cancer. 72% reported ever having a PSA. Older age.– 73% within 1 year.Urinary symptoms.– 23% 1–2 years ago.71% reported their physician had spoken to them about prostate cancer screening.– 4% >2 years ago.DRE 90% reported ever having had a DRE.– 60% within 1 year.– 23% 1–2 years ago.– 17% >2 years ago.Unaffected men with and without a first-degree relative with prostate cancer.^29,166 men aged 40–80 years (83 men with a first-degree relative; 83 men with no family history).PSA Family history of prostate cancer. First degree-relative: 72% reported ever having had a PSA. Greater perceived vulnerability to developing prostate cancer.No family history: 53% reported ever having had a PSA.French brothers or sons of men with prostate cancer.^30,420 men aged 40–70 years.PSA Younger age.88% adhered to annual PSA screening.Greater number of relatives with prostate cancer.Increased anxiety.Married.Higher education.Previous history of prostate cancer screening.Unaffected African American men participating in a hereditary prostate cancer study and data from the 1998 and 2000 NHIS.^31,Unaffected men aged 40–69 years (134 men with a family history of ≥4 men with prostate cancer; 5,583 men from 1998 NHIS [for DRE] including 683 African American men and 4,900 Caucasian men; 3,359 men from 2000 NHIS [for PSA] including 411 African American men and 2,948 Caucasian men).PSA Younger age.Family Study Cohort:Fewer number of relatives with prostate cancer.45% reported ever having had a PSA. African American men in NHIS:65% reported ever having had a PSA.DRE Family Study Cohort:35% reported ever having had a DRE.African American men in NHIS:45% reported ever having had a DRE.

Quality of Life in Relation to Screening for Prostate Cancer Among Individuals at Increased Hereditary Risk

Concern about developing prostate cancer: Although up to 50% of men in some studies who were first-degree relatives of prostate cancer patients expressed some concern about developing prostate cancer,⁴ the level of anxiety reported is typically relatively low and is related to lifetime risk rather than short-term risk.^2,4 The concern is also higher in men who are younger than their first-degree relative was at the time when their prostate cancer was diagnosed.⁴ First-degree relatives who were unmarried worried more about developing prostate cancer than did married men.⁴ Men with higher levels of concern about developing prostate cancer also had higher estimates of personal prostate cancer risk and a larger number of relatives diagnosed with prostate cancer.⁴ In a Swedish study, only 3% of the 110 men surveyed said that worry about prostate cancer affected their daily life “fairly much,” and 28% said it affected their daily life "slightly."^2,

Baseline distress levels: Distress, both general and prostate cancer–related, did not differ significantly between men who were first-degree relatives of prostate cancer patients and men who were not who self-referred for free prostate cancer screening.³² Men with a family history of prostate cancer in the study had higher levels of perceived risk. In a Swedish study, male first-degree relatives of prostate cancer patients who reported more worry about developing prostate cancer had higher Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores than men with lower levels of worry. In that study, the average HADS depression and anxiety scores among first-degree relatives was at the 75th percentile. Depression was associated with higher levels of personal risk overestimation.^2,

Distress experienced during prostate cancer screening: A study measured the anxiety and general quality of life experienced by 220 men with a family history of prostate cancer while undergoing prostate cancer screening with PSA tests.²⁸ In this group, 20% of the men experienced a moderate deterioration in their anxiety scores, and 20% experienced a minimal deterioration in health-related quality of life (HRQOL). The average period between assessments was 35 days, which encompassed PSA testing and a wait for results that averaged 15.6 days. Only men with normal PSA values (4 ng/mL or less) were assessed. Factors associated with deterioration in HRQOL included being 50 to 60 years of age, having more than 2 relatives with prostate cancer, having an anxious personality, being well-educated, and having no children presently living at home. These authors stress that analysis of the impact of screening on first-degree relatives should not rely solely on mean changes in scores, which may “mask diversity among responses, as illustrated by the proportion of subjects worsening during the screening process.” Given that these were men receiving what was considered a normal result and that a subset of men experienced screening-associated distress, this study suggests that interventions to reduce screening-related distress may be needed to encourage men at increased hereditary risk to comply with repeated requests for screening.

A study in the United Kingdom assessed predictors of psychological morbidity and screening adherence in first-degree relatives of men with prostate cancer participating in a PSA screening study. One hundred twenty-eight first-degree relatives completed measures assessing psychological morbidity, barriers, benefits, knowledge of PSA screening, and perceived susceptibility to prostate cancer. Overall, 18 men (14%) scored above the threshold for psychiatric morbidity, consistent with normal population ranges. Cancer worry was positively associated with health anxiety, perceived risk, and subjective stress. However, psychological morbidity did not predict PSA screening adherence. Only past screening behavior was found to be associated with PSA screening adherence.^33,

¹ Weinrich SP, Weinrich MC, Boyd MD, et al.: The impact of prostate cancer knowledge on cancer screening. Oncol Nurs Forum 25 (3): 527-34, 1998.

² Bratt O, Damber JE, Emanuelsson M, et al.: Risk perception, screening practice and interest in genetic testing among unaffected men in families with hereditary prostate cancer. Eur J Cancer 36 (2): 235-41, 2000.

³ Cormier L, Kwan L, Reid K, et al.: Knowledge and beliefs among brothers and sons of men with prostate cancer. Urology 59 (6): 895-900, 2002.

⁴ Beebe-Dimmer JL, Wood DP Jr, Gruber SB, et al.: Risk perception and concern among brothers of men with prostate carcinoma. Cancer 100 (7): 1537-44, 2004.

⁵ Miller SM, Diefenbach MA, Kruus LK, et al.: Psychological and screening profiles of first-degree relatives of prostate cancer patients. J Behav Med 24 (3): 247-58, 2001.

⁶ Montgomery GH, Erblich J, DiLorenzo T, et al.: Family and friends with disease: their impact on perceived risk. Prev Med 37 (3): 242-9, 2003.

⁷ Doukas DJ, Fetters MD, Coyne JC, et al.: How men view genetic testing for prostate cancer risk: findings from focus groups. Clin Genet 58 (3): 169-76, 2000.

⁸ Diefenbach MA, Schnoll RA, Miller SM, et al.: Genetic testing for prostate cancer. Willingness and predictors of interest. Cancer Pract 8 (2): 82-6, 2000 Mar-Apr.

⁹ Bratt O, Kristoffersson U, Lundgren R, et al.: Sons of men with prostate cancer: their attitudes regarding possible inheritance of prostate cancer, screening, and genetic testing. Urology 50 (3): 360-5, 1997.

¹⁰ Lee SC, Bernhardt BA, Helzlsouer KJ: Utilization of BRCA1/2 genetic testing in the clinical setting: report from a single institution. Cancer 94 (6): 1876-85, 2002.

¹¹ Jacobsen PB, Valdimarsdottier HB, Brown KL, et al.: Decision-making about genetic testing among women at familial risk for breast cancer. Psychosom Med 59 (5): 459-66, 1997 Sep-Oct.

¹² Lerman C, Schwartz MD, Lin TH, et al.: The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol 65 (3): 414-20, 1997.

¹³ Rimer BK, Schildkraut JM, Lerman C, et al.: Participation in a women's breast cancer risk counseling trial. Who participates? Who declines? High Risk Breast Cancer Consortium. Cancer 77 (11): 2348-55, 1996.

¹⁴ Struewing JP, Lerman C, Kase RG, et al.: Anticipated uptake and impact of genetic testing in hereditary breast and ovarian cancer families. Cancer Epidemiol Biomarkers Prev 4 (2): 169-73, 1995.

¹⁵ Lerman C, Daly M, Masny A, et al.: Attitudes about genetic testing for breast-ovarian cancer susceptibility. J Clin Oncol 12 (4): 843-50, 1994.

¹⁶ Miesfeldt S, Jones SM, Cohn W, et al.: Men's attitudes regarding genetic testing for hereditary prostate cancer risk. Urology 55 (1): 46-50, 2000.

¹⁷ Weinrich S, Royal C, Pettaway CA, et al.: Interest in genetic prostate cancer susceptibility testing among African American men. Cancer Nurs 25 (1): 28-34, 2002.

¹⁸ Doukas DJ, Li Y: Men's values-based factors on prostate cancer risk genetic testing: a telephone survey. BMC Med Genet 5: 28, 2004.

¹⁹ Myers RE, Hyslop T, Jennings-Dozier K, et al.: Intention to be tested for prostate cancer risk among African-American men. Cancer Epidemiol Biomarkers Prev 9 (12): 1323-8, 2000.

²⁰ Li Y, Doukas DJ: Health motivation and emotional vigilance in genetic testing for prostate cancer risk. Clin Genet 66 (6): 512-6, 2004.

²¹ Meiser B, Dunn S: Psychological impact of genetic testing for Huntington's disease: an update of the literature. J Neurol Neurosurg Psychiatry 69 (5): 574-8, 2000.

²² Lerman C, Shields AE: Genetic testing for cancer susceptibility: the promise and the pitfalls. Nat Rev Cancer 4 (3): 235-41, 2004.

²³ Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992.

²⁴ Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993.

²⁵ Vadaparampil ST, Jacobsen PB, Kash K, et al.: Factors predicting prostate specific antigen testing among first-degree relatives of prostate cancer patients. Cancer Epidemiol Biomarkers Prev 13 (5): 753-8, 2004.

²⁶ Bock CH, Peyser PA, Gruber SB, et al.: Prostate cancer early detection practices among men with a family history of disease. Urology 62 (3): 470-5, 2003.

²⁷ Horowitz M, Wilner N, Alvarez W: Impact of Event Scale: a measure of subjective stress. Psychosom Med 41 (3): 209-18, 1979.

²⁸ Cormier L, Reid K, Kwan L, et al.: Screening behavior in brothers and sons of men with prostate cancer. J Urol 169 (5): 1715-9, 2003.

²⁹ Jacobsen PB, Lamonde LA, Honour M, et al.: Relation of family history of prostate cancer to perceived vulnerability and screening behavior. Psychooncology 13 (2): 80-5, 2004.

³⁰ Roumier X, Azzouzi R, Valéri A, et al.: Adherence to an annual PSA screening program over 3 years for brothers and sons of men with prostate cancer. Eur Urol 45 (3): 280-5; author reply 285-6, 2004.

³¹ Weinrich SP: Prostate cancer screening in high-risk men: African American Hereditary Prostate Cancer Study Network. Cancer 106 (4): 796-803, 2006.

³² Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999.

³³ Sweetman J, Watson M, Norman A, et al.: Feasibility of familial PSA screening: psychosocial issues and screening adherence. Br J Cancer 94 (4): 507-12, 2006.

Disclaimer

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

Changes to This Summary (06/26/2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Introduction

Added text about the results of a segregation analysis of 1,546 families from Finland (cited Pakkanen et al. as reference 52).

Prostate Cancer Susceptibility Loci

Added text about studies that confirmed the association between prostate cancer risk and 8q24 single nucleotide polymorphisms and variants (cited Schumacher et al. as reference 76, Suuriniemi et al. as reference 77, Wang et al. as reference 78, Yeager et al. as reference 79, Gudmundsson et al. as reference 80, and Haiman et al. as reference 81).

Added OMIM links for genes in Table 2 and Table 3.

Added text about the results of a study of BRCA2 mutations and susceptibility to hereditary prostate cancer (cited Agalliu et al. as reference 96).

Added text about the results of a Polish study that examined CHEK2 gene mutations and susceptibility to prostate cancer (cited Cybulski et al. as reference 110).

Added text about a fine mapping study that localized a prostate cancer predisposition gene to an 880-kb region on chromosome 22q12.3 (cited Camp et al. as reference 118).

Added text about results of a genome-wide linkage study that examined hereditary prostate cancer families with primary kidney cancer (cited Johanneson et al. as reference 120).

Polymorphisms and Prostate Cancer Susceptibility

Added text about the results of a case-control study that examined BCL-2 sequence variants and inherited predisposition to prostate cancer (cited Kidd et al. as reference 26).

Interventions in Familial Prostate Cancer

Added text about a longitudinal report that addresses whether family history of prostate cancer is linked with aggressive tumor behavior (cited Kupelian et al. as reference 20).

Psychosocial Issues in Prostate Cancer

Added Table 6 to replace text that summarizes studies of behavioral correlates for prostate cancer screening.

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