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.

⁶⁹ Seppälä EH, Ikonen T, Autio V, et al.: Germ-line alterations in MSR1 gene and prostate cancer risk. Clin Cancer Res 9 (14): 5252-6, 2003.

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⁷¹ Miller DC, Zheng SL, Dunn RL, et al.: Germ-line mutations of the macrophage scavenger receptor 1 gene: association with prostate cancer risk in African-American men. Cancer Res 63 (13): 3486-9, 2003.

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.

⁷⁹ Yeager M, Orr N, Hayes RB, et al.: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39 (5): 645-649, 2007.

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.

¹¹² Ford D, Easton DF, Stratton M, et al.: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3): 676-89, 1998.

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.

¹¹⁵ Larson GP, Ding Y, Cheng LS, et al.: Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT. Cancer Res 65 (3): 805-14, 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 p