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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.
Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.
The public health burden of prostate cancer is substantial. A total of 233,000 new cases of prostate cancer and 29,480 deaths from the disease are anticipated in the United States in 2014, making it the most frequent nondermatologic cancer among U.S. males.[1] A man's lifetime risk of prostate cancer is one in seven. 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 cases 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 than white men.[4]
These differences may be due to the interplay of genetic, environmental, and social influences (such as access to health care), which may affect the development and progression of the disease.[5] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[6] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular genetics of prostate cancer is still limited. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[7]
Risk Factors for Prostate Cancer
The three most important recognized risk factors for prostate cancer in the United States are:
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 298 for men 49 years or younger, 1 in 43 for men aged 50 through 59 years, 1 in 16 for men aged 60 through 69 years, and 1 in 9 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 7.[1]
The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[8,9] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[10]
Family history of prostate cancer
As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[11,12,13,14,15] From 5% to 10% of prostate cancer cases are believed to be primarily caused by 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.[12,16,17] 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.[13,14,15,16,17] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[18]
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], 1.8–5.9) for prostate cancer among men with a family history of the disease.[19] 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 to 86 years who had been randomly selected as controls for a population-based case-control study conducted in Iowa from 1987 to 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).[20]
A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. (See Table 1 for a summary of the RRs related to a family history of prostate cancer.)[21]
Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[22] The size of this data set, with its nearly 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. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% CI, 2.05–2.20) with an affected father only, 2.96 (95% CI, 2.80–3.13) with an affected brother only, and 8.51 (95% CI, 6.13–11.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.26–25.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.
A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[23] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).
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).[19] Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[19,24] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[25] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the increased risk of prostate cancer among men with BRCA1/BRCA2mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[26,27,28,29] (Refer to the BRCA1 and BRCA2 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 (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[30] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian Americans than among African Americans or whites. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.9–3.3) with adjustment for age and ethnicity.[30]
Evidence for inherited forms of prostate cancer can be found in several U.S. and international studies.[12,16,31,32,33,34] It was first noted in 1956 that men with prostate cancer reported a higher frequency of the disease among relatives than did controls.[35] 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.[36]
Other potential modifiers of prostate cancer risk
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.[37] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[38] including the potential role of the androgen receptor (AR) CAG repeat length in exon 1. This modulates AR activity, which may influence prostate cancer risk.[39] For example, a meta-analysis reported that AR CAG repeat length greater than or equal to 20 repeats conferred a protective effect for prostate cancer in subsets of men.[40]
Some dietary risk factors may be important modulators of prostate cancer risk; these include fat and/or meat consumption,[41] lycopene,[42,43] and dairy products/calcium/vitamin D.[44] Phytochemicals are plant-derived nonnutritive compounds, and it has been proposed that dietary phytoestrogens may play a role in prostate cancer prevention.[45] 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.[46] Several studies have suggested that vasectomy increases the risk of prostate cancer,[47] but other studies have not confirmed this observation.[48] Obesity has also been associated with increased risk of advanced stage at diagnosis, prostate cancer metastases, and prostate cancer–specific death.[49,50]
Other nutrients have been studied for their potential influence on prostate cancer risk. The effect of selenium and vitamin E in preventing prostate cancer was studied in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). This randomized placebo-controlled trial of selenium and vitamin E among 35,533 healthy men found no evidence of a reduction in prostate cancer risk,[51] although a statistically significant increase (HR, 1.17; 99% CI, 1.004–1.36; P = .008) in prostate cancer with vitamin E supplementation alone was observed.[52] The absolute increased risk associated with vitamin E supplementation compared to placebo after more than 7 years of follow-up was 1.6 per 1,000 person years.
(Refer to the PDQ summary on Prevention of Prostate Cancer for more information about risk factors for prostate cancer in the general population.)
Multiple Primaries
The Surveillance, Epidemiology and End Result Cancer Registries has assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 5.01–5.4). There was a significant risk of new malignancies (all cancers combined) among men diagnosed prior to age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus, and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer.[53]
The underlying etiology of developing a second primary cancer after prostate cancer may be related to various factors. Some of the observed excess risks could be associated with prior radiation therapy. Radiation therapy as the initial treatment for prostate cancer was found to increase the risk of bladder and rectal cancers and cancer of the soft tissues. More than 50% of the small intestine tumors were carcinoid malignancies, suggesting possible hormonal influences. The excess of pancreatic cancer may be due to mutations in BRCA2, which predisposes to both. The risk of melanoma was most pronounced in the first year of follow-up after diagnosis, raising the possibility that this is the result of increased screening and surveillance.[53]
One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer following prostate cancer. Of 18,207 men with prostate cancer, 560 developed a second primary malignancy. Of those, the relative risk (RR) was increased for colorectal, kidney, bladder, and squamous cell skin cancers. Having a paternal family history of prostate cancer was associated with an increased risk of bladder cancer, myeloma, and squamous cell skin cancer. Among prostate cancer probands, those with a family history of colorectal cancer, bladder cancer, or chronic lymphoid leukemia were at increased risk of that specific cancer as a second primary cancer.[54]
Risk of Other Cancers in Multiple-Case Families
Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[55,56,57]
In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (standardized incidence ratio [SIR], 1.9; 95% CI, 1.0–3.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer site–specific disorder.[58]
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% (95% CI, 29–50) of prostate cancer risk may be accounted for by heritable factors.[59] This is in agreement with a previous U.S. study that showed a concordance of 7.1% between dizygotic twin pairs and a 27% concordance between monozygotic twin pairs.[60] 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).[12] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[61]
Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[62,63,64] 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 in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[60] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [65,66,67,68] 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) than noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[69]
Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, highly penetrant in families, and have large effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.
Linkage Analyses
Introduction to linkage analyses
The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.
Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:
Furthermore, because a standard definition of hereditary prostate cancer (HPC) has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of HPC families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have HPC:
Using these criteria, surgical series have reported that approximately 3% to 5% of men will be from a family with HPC.[2,3]
An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a man's lifetime risk of prostate cancer is one in seven[4], it is possible that families under study have men with both inherited and sporadic prostate cancer. 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 limited 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 PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.
One way to address inconsistencies between linkage studies is to require inclusion criteria that defines clinically significant disease (e.g., Gleason score ?7, PSA ?20 ng/mL) in an affected man.[5,6,7] 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.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]
Susceptibility loci identified in linkage analyses
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 described above. Data on the proposed phenotype associated with each locus are also limited, 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.
Other genetic loci discovered by linkage analysis
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 (logarithm of the odds [LOD] score ?2) include the following chromosomes:
Linkage analyses in various familial phenotypes
Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.
Linkage analysis in African American families
The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint heterogeneity LOD (hLOD) scores of 1.3 to 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 = 1.08) and 22q12 (multipoint hLOD score = 0.91).[93,99] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (hLOD = 1.97) and 12q24 (hLOD = 2.21) using a 6,000 single nucleotide polymorphism (SNP) platform.[110] Further study including a larger number of African American families is needed to confirm these findings.
Linkage analysis in families with aggressive prostate cancer
In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (hLOD score = 2.18) and 22q12.3-q13.1 (hLOD score = 1.90).[5] 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.[106] An analysis of high-risk pedigrees from Utah provides an overview of this strategy.[111] A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer.[44] Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.09–3.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.
Linkage analysis in families with multiple cancers
In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic.[112] 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 HPC and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[113] This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 HPC families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.[112]
Summary of prostate cancer linkage studies
Linkage to chromosome 17q21-22 and subsequent fine-mapping and exome sequencing have identified recurrent mutations in the HOXB13 gene to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility of testing for HOXB13 mutations has not yet been defined. Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table 2), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.
Case-Control Studies
A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[114,115]
Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[114,115]
Genes interrogated in case-control studies
Androgen receptorgene
Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[117] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[118]
Altered activity of the AR caused by inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[119,120] 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.[117,119,120,121,122,123,124,125,126,127,128,129] 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 one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[130] Subsequently, the large multiethnic cohort study 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.[131] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles, with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.08–1.69; P = .03).[132]
An analysis of AR gene CAG and CGN repeat length polymorphisms targeted African American men from the Flint Men's Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[133] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[131,134,135] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.
Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[136] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[137] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.
A study of genomic DNA from 60 multiple-case African American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[138]
Steroid 5-alpha-reductase 2gene (SRD5A2)
Molecular epidemiology studies have also examined genetic polymorphisms of the steroid 5-alpha-reductase 2 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 dihydrotestosterone (DHT) by 5-alpha-reductase type II.[139] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[140,141]
A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[142] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[139,143] 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.[117,139] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[144] This meta-analysis also examined the potential roles of two 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 and 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).[132] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.09–2.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.14–2.68).[145] A subsequent systematic review and meta-analysis including 27 nonfamilial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[146]
Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.35–0.88; OR, 0.57; 95% CI, 0.36–0.90; OR, 0.55; 95% CI, 0.35–0.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.94–2.63).[147] Additional studies are needed to confirm these findings.
Estrogen receptor-betagene
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 SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[148] This study awaits replication.
E-cadherin is a tumor suppressor gene in which germline mutations cause a hereditary form of gastric carcinoma. A SNP designated -160?A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene. Because somatic mutations in E-cadherin have been implicated in development of invasive malignancy in a number of different cancers, various investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 26 case-control studies evaluated this genetic variant as a candidate susceptibility allele for seven different cancers.[149] Eight of these studies (~2,600 cases and 2,600 controls) evaluated the risk of prostate cancer. Overall, carriers of the -160?A allele were at 30% increased risk of prostate cancer (95% CI, 1.1–1.6) compared with controls. A second meta-analysis [150] of E-cadherin associations with prostate cancer, reported findings that were quite similar to those noted above,[149] although the overall association between the -160?A allele was not statistically significant (OR, 1.21; 95% CI, 0.97–1.51). The second study was based on a set of individual studies that largely, but not completely, overlapped with those in the earlier report; it was the exclusion of a study judged to have inappropriate controls [150] that accounts for this difference. The overlap in individual studies included in these two meta-analyses is large; therefore, the second meta-analysis does not represent confirmation of the first. Further studies are required to determine whether this finding is reproducible and biologically/clinically important.
Toll-like receptor genes
There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[151] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[152] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[153,154,155,156,157] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.
One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[158] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.33–0.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.
Other genes and polymorphisms interrogated for risk
SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a sample of individuals with primarily Caucasian ancestry.[159] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk of prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic white men, Hispanic white men, and African American men.[160] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic whites (P = .001). In non-Hispanic whites, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < .001). In African Americans, SNPs within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1 showed a significant interaction (P = .014). In non-Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at three SNPs in HSD3B2 and CYP19 (OR, 2.20; 95% CI, 1.44–3.38; P = .0003). In Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at two SNPs in CYP19 and CYP24A1 (OR, 4.29; 95% CI, 2.11–8.72; P = .00006). While this study did not evaluate all potentially important SNPs in genes in the steroid hormone pathway, it demonstrates how studies can be performed to evaluate multigenic effects in multiple populations to assess the contribution to prostate cancer risk.
A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in white men.[161]
Four SNPs in the p53 pathway (three in genes regulating p53 function including MDM2, MDM4, and HAUSP and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[162] However, a subsequent meta-analysis of case-control studies that focused on MDM2 (T309G) and prostate cancer risk revealed no association.[163] Therefore, the biologic basis of the various associations identified requires further study.
Table 3 summarizes additional case-control studies that have assessed genes that are potentially associated with prostate cancer susceptibility.
Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBS1, CHEK2, AR, SRD5A2, ER-beta, E-cadherin, and the toll-like receptor genes. These studies have been complicated by the later-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 HPC, as suggested by both segregation and linkage studies. In this respect, HPC 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, Lynch syndrome, hereditary melanoma, and hereditary renal cancer). The clinical validity and utility of genetic testing for any of these genes based solely on evidence for HPC susceptibility has not been established.
Admixture Mapping
Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[175] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared to another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[176,177]
Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African Americans. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:
An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[179] As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.[176] (Refer to the GWAS section of this summary for more information.)
Genome-wide Association Studies (GWAS)
Introduction to GWAS
Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[180] including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[181,182] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to "scan" the genome without having to test all tens of millions of known SNPs. GWAS can test approximately 1 million SNPs and ascertain almost all common inherited variants in the genome.
In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signals–in which allele frequencies deviate significantly in case and control populations–are validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNPs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently whenstandard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P < 1 × 10-7.[183,184,185]
To date, approximately 80 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 4). These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:
The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[188]
Candidate genes and susceptibility loci identified in GWAS
In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men.[69] In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus.[68] Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737.[68] The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%.[68] These results were confirmed in several large, independent cohorts.[70,71,72,73,80,81,82,83,189] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[73,74,75] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54–128.62 Mb, region 2 at 128.14–128.28 Mb, and region 3 (containing rs6983267) at 128.47–128.54 Mb.[75] Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[86,87]
Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for men of European ancestry are included in Table 4. The association between risk and allele status for each variant listed in Table 4 reached genome-wide statistical significance in more than one independent cohort.
GWAS in populations of non-European ancestry
Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups. Most work in this regard has focused on African American, Chinese, and Japanese men.
The African American population is of particular interest because American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease.[69] A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[200] On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P ? .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.
This analysis was followed by a GWAS to discover risk variants not previously identified in GWAS performed in other ethnicities.[201] The GWAS was conducted in a standard multistage fashion in which 3,621 African American cases and 3,502 controls were genotyped for approximately 1 million SNPs. SNPs meeting proscribed statistical thresholds were selected for a second stage in 1,396 cases and 2,383 controls (known prostate cancer risk SNPs were excluded, as they had been rigorously analyzed, as described above). One marker–rs7210100 at chromosome 17q21–emerged and remained significant when tested in a third stage with 3,471 cases and 904 controls. When combining cases and controls from all three stages, prostate cancer risk in heterozygote and homozygote carriers of the rs7210100 risk allele was 1.49 and 2.73, respectively (P = 3.4 × 10-13). The risk allele is uncommon in African Americans (4%–7% frequency) but is virtually nonexistent in men of European ancestry. The SNP may therefore account for some ethnic difference in risk. The SNP resides in intron 1 on the gene ZNF652. Co-expression of ZNF652 and the AR in prostate tumors has been associated with a decrease in relapse-free survival, which may suggest a mechanism of action if this variant influences expression.
A case-control study evaluated GWAS-identified prostate cancer–associated genetic markers at chromosomal region 8q24 in men of African ancestry in Tobago, Republic of Trinidad and Tobago.[202] Among 354 cases and 438 controls, rs16901979 was significantly associated with prostate cancer risk (OR, 1.41; 95% CI, 1.02–1.95; P = .04), with higher associated risk in men with early-onset prostate cancer (OR, 2.37; 95% CI, 1.40–3.99; P = .001).
Similar work has been accomplished in the Japanese population. Twenty-three candidate SNPs related to prostate cancer risk in two GWAS studies of European populations were evaluated in a relatively small population of Japanese cases (n = 311) and controls (n = 1,035).[203] Seven of these SNPs (from five genetic loci) were associated with prostate cancer risk (OR, 1.35–1.82). Men with six or more risk alleles (27% of cases and 11% of controls) had a sixfold greater prostate cancer risk than those with two or fewer risk alleles (7% of cases and 20% of controls [OR, 6.22; P = 1.5 × 10-12]). To further assess susceptibility loci in a Japanese population, a two-stage GWAS was conducted using a total of 4,584 Japanese men with prostate cancer and 8,801 controls.[204] The study resulted in the identification of five SNPs from five separate loci not previously associated with prostate cancer: rs13385191 at 2p24 (OR, 1.15); rs12653946 at 5p15 (OR, 1.26); rs1983891 at 6p21 (OR, 1.15); rs339331 at 6q22 (OR, 1.22); and rs9600079 at 13q22 (OR, 1.18) [data after combining cohorts from both stages of the study]. A set of nine SNPs that were nominally associated with disease risk in the initial GWAS were subsequently analyzed in other large Japanese cohorts and then united with the original cases and controls in a meta-analysis (7,141 prostate cancer cases and 11,804 controls).[205] This study revealed three new prostate cancer risk loci in this ancestral population: rs1938781 at 11q12 (OR, 1.16); rs2252004 at 10q26 (OR, 1.16); and rs2055109 at 3p11.2 (OR, 1.20).
These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.
Clinical application of GWAS findings
Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region.[78] Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 × 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.93–6.80; P = 1.20 × 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.62–24.72; P = 1.29 × 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.
A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.64–6.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.83–5.33).[206]
However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected.[78] The addition of more recently discovered SNPs to the model has not appreciably improved these results.[207] While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.[208]
Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.[209]
In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[208] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have "poor discriminative ability" to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional "common" risk alleles (alleles carried by >1%–5% of individuals within the population).[210]
GWAS findings to date account for only a fraction of heritable risk of disease. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with higher ORs for risk. For example, a consortium led by deCODE genetics in Iceland performed whole-genome sequencing of 2,500 Icelanders and identified approximately 32.5 million variants, including millions of rare variants (carried by <1% of the population). These variants were analyzed in 5,141 prostate cancer cases and 54,444 controls (genotypes were imputed in cases in which they had not been genotyped in previous analyses). In addition to previously reported risk alleles at 8q24 and 17q12, significant associations with prostate cancer were observed for two rare 8q24 SNPs—the minor allele (the G allele) of rs183373024 (OR, 2.69; P = 1.5 × 10?23) and the minor allele (the A allele) of rs188140481 (OR, 2.88; P = 1.5 × 10?22).[211] These results were validated in independent cohorts of European cases and controls. The frequencies of the risk alleles of these two variants in controls ranged from 0.1% to 1.1% and were lowest in southern Europe and highest in northern Europe. These data, in which risk alleles had high ORs compared with previous GWAS, demonstrate that the bulk of inherited risk may reside in rare alleles.
In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.
GWAS and insight into the mechanism of prostate cancer risk
Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:
The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci.[213] Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[214,215,216] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC.[217] Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[215,217] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.
Modified approaches to GWAS
A 2012 study used a novel approach to identify polymorphisms associated with risk.[218] On the basis of the well-established principle that the AR plays a prominent role in prostate tumorigenesis, the investigators targeted SNPs that reside at sites where the AR binds to DNA. They leveraged data from previous studies that mapped thousands of AR binding sites genome-wide in prostate cancer cell lines to select SNPs to genotype in the Johns Hopkins Hospital cohort of 1,964 cases and 3,172 controls and the Cancer Genetic Markers of Susceptibility cohort of 1,172 cases and 1,157 controls. This modified GWAS revealed a SNP (rs4919743) located at the KRT8 locus at 12q13.13—a locus previously implicated in cancer development—associated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.13–1.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants.
Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[219] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.
Inherited Variants Associated With Prostate Cancer Aggressiveness
Due to the screening-related debate over risk of identifying clinically insignificant prostate cancers and the potential for overtreatment, studies characterizing genetic variants in subsets of patients with aggressive disease (e.g., Gleason score ?8) are now being reported.
One study evaluated the association between the CASP8 D302H polymorphism and aggressive prostate cancer in a pooled analysis from three studies including 796 aggressive prostate cancer cases and 2,060 controls.[220] Aggressive disease was defined as having androgen ablation therapy for prostate cancer, a PSA level greater than 50 ng/mL, radiographic evidence of metastases, or a Gleason score of 8 to 10. The H allele was associated with a protective effect for aggressive prostate cancer (OR per allele, 0.67; 95% CI, 0.54–0.83, P = .0003). The results were similar for European Americans and African Americans. The protective effect was observed only for aggressive disease, not for prostate cancer risk overall or for indolent prostate cancer, implying potential utility in identifying patients at risk of clinically significant disease.
A second study focused on germline polymorphisms residing in the gene C-C chemokine ligand 2 (CCL2).[221] This gene appears to play a role in prostate cancer tumorigenesis and invasion. In a cohort of 4,073 European American men with prostate cancer, inheriting the CCL2 -1181 G allele (AG or GG genotype) was associated with advanced pathologic stage (OR, 1.50; 95% CI, 1.03–2.18; P = .04) and higher Gleason score (OR, 1.47; 95% CI, 1.08–2.01; P = .01), compared with the AA genotype.
Four SNPs in the p53 pathway (three in genes regulating p53 function including Mdm2, Mdm4, and Hausp and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[162] The biologic basis of the various associations identified requires further study, and validation of these findings is needed.
Twenty prostate cancer risk SNPs identified in GWAS and fine-mapping follow-up studies were evaluated in 5,895 prostate cancer patients in search of SNP associations with prostate cancer aggressiveness.[222] The risk-associated alleles of two SNPs (rs2735839 in KLK3 and rs10993994 in MSMB) were significantly associated with less aggressive prostate cancer; no significant associations were observed for the other 18 candidate SNPs. Similarly, in a larger cohort from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium that included 10,501 prostate cancer cases and 10,831 controls, the rs2735839 risk allele was associated with less aggressive disease.[223] The two SNPs are known to be associated with PSA levels in normal men without prostate cancer. The authors concluded that the observed associations may be driven by over-representation within their case series of PSA screen-detected low-grade/low-stage disease and that none of these risk-related SNPs appear to hold the potential for identifying men at increased genetic risk of more aggressive prostate cancer.
A single institution study evaluated 36 SNPs for association with disease aggressiveness and prostate cancer–specific mortality in a prostate cancer cohort including 3,945 cases (predominantly European ancestry) and 580 prostate cancer–specific deaths.[224] Two SNPs were associated with prostate cancer–specific survival (rs2735839 at 19q13, P = 7 × 10-4 and rs7679673 at 4q24, P = .014). Twelve SNPs were associated (P < .05) with other measures of prostate cancer aggressiveness, including age at diagnosis, PSA level at diagnosis, Gleason score, and D'Amico criteria.[225] These results need confirmation, as adjustment for multiple testing was not performed and ascertainment bias from single institution referral and screening patterns may have influenced the findings.
Interestingly, in the retrospective series above, the prostate cancer risk allele at rs2735839 was associated with lower PSA levels and less aggressive disease.[193,226] A hypothesis explaining this phenomenon is that those carrying the allele associated with aggressiveness generally have lower PSAs, are sent for prostate biopsy less often, and are diagnosed later in the natural history of the disease.
One study evaluated the risk of metastatic prostate cancer (470 incident metastatic prostate cancer cases and 1,945 controls) and prostate cancer recurrence after prostatectomy for localized disease (1,412 localized prostate cancer cases, 328 of which had recurrence) with 12 SNPs previously found to be associated with prostate cancer risk.[227] The T allele of rs10993994 in MSMB was associated with increased metastatic prostate cancer risk (RR, 1.24; 95% CI, 1.05–1.48; P = .012). The authors hypothesize that this SNP could be associated with primary carcinogenesis because metastatic prostate cancer at the time of diagnosis is less likely to be associated with PSA screen–detected disease. The other significant finding was the association in 8q24 of the A allele of rs4242382 (RR, 1.40; 95% CI, 1.13–1.75) and inverse association of the T allele of rs6938267 (RR, 0.67; 95% CI, 0.50–0.89) with metastatic prostate cancer. None of the SNPs studied were associated with risk of recurrence. These findings were not consistent with results of similar retrospective series.[224,228]
The association between prostate cancer–specific mortality (PCSM) and 846 SNPs was studied in a population-based prostate cancer cohort of 1,309 individuals in Seattle.[229] Twenty-two SNPs found to be significantly associated with PCSM were then studied in a validation cohort of 2,875 prostate cancer cases from Sweden, of which five SNPs were significantly associated with PCSM. Hazard ratios (HRs) in the Swedish validation cohort after adjusting for age at diagnosis, Gleason score, stage, PSA at diagnosis, and treatment for three of the SNPs were as follows: rs1137100 (LEPR) (HR, 0.82; 95% CI, 0.67–1.00; P = .027); rs2070874 (IL4) (HR, 1.27; 95% CI, 1.04–1.56, P = .011); and rs10778534 (CRY1) (HR, 1.23; 95% CI, 1.00–1.51, P = .022). Two of the SNPs were validated after adjusting for age at diagnosis alone: rs627839 (RNASEL) (HR, 1.22; 95% CI, 1.00–1.50, P = .024) and rs5993891 (ARVCF) (HR, 0.72; 95% CI, 0.52–1.01, P = .024). Compared with patients with zero to two at-risk genotypes, there was an increase in risk observed in patients with a greater number of at-risk genotypes after adjusting for age at diagnosis, Gleason score, stage, PSA at diagnosis, and treatment as follows: three at-risk genotypes (HR, 1.05; 95% CI 0.81–1.37); four at-risk genotypes (HR, 1.51; 95% CI, 1.16–1.97); and five at-risk genotypes (HR, 1.46 95% CI, 0.97–2.19). These results need validation for informing patient risk assessment and management.
To definitively identify the inherited variants associated with prostate cancer aggressiveness, well-powered GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. The control arm of such a study could be comprised of age-matched controls with no evidence of the disease or men with low-grade, indolent disease. One underpowered study genotyped 202 aggressive cases and 100 men matched by PSA and age who had not developed the disease using a SNP panel of 387,384 polymorphisms.[230] Results were validated in a cohort of 527 aggressive cases, 595 less-aggressive cases, and 1,167 controls. The GWAS produced one SNP, rs6497287 at chromosome 15q13, as associated with aggressive disease. These results require further validation but point to the potential for GWAS focusing on this important phenotype.
While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore it is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.
Studies of male BRCA1[1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2]
BRCAmutation–associated prostate cancer risk
The risk of prostate cancer in BRCA mutation carriers has been studied in various settings.
In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 5.
Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[5] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.
Prevalence ofBRCAfounder mutations in men with prostate cancer
Ashkenazi Jewish
Several studies in Israel and in North America have analyzed the frequency of BRCAfounder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[6,7,8] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of AJ 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% confidence interval [CI], 0.2–0.4) for the 5382insC mutation, and 1.3% (95% CI, 1.0–1.5) for the BRCA2 6174delT mutation.[9,10,11,12] (Refer to the High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Ovarian Cancer for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks 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 the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia, area 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) among carriers and 3.8% among noncarriers (95% CI, 3.3–4.4).[12] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by age 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]).
The studies summarized in Table 6 used similar case-control methods to examine 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.
These studies support the hypothesis that prostate cancer occurs excessively among carriers of AJ founder mutations and suggest that the risk may be greater among men with the BRCA2 founder mutation (6174delT) than among 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. Some data suggest that BRCA-related prostate cancer has a significantly worse prognosis than prostate cancer that occurs among noncarriers.[16]
Other populations
The association between prostate cancer and mutations in BRCA1 and BRCA2 has also been studied in other populations. Table 7 summarizes studies that used case-control methods to examine the prevalence of BRCA mutations among men with prostate cancer from other varied populations.
These data suggest that prostate cancer risk in BRCA1/2 mutation carriers varies with the location of the mutation (i.e., there is a correlation between genotype and phenotype).[17,18,19] These observations might explain some of the inconsistencies encountered in prior studies of these associations, since varied populations may have differences in the proportion of persons with specific pathogenic BRCA1/2 mutations.
Several case series have also explored the role of BRCA1 and BRCA2 mutations and prostate cancer risk.
These case series confirm that mutations in BRCA1 and BRCA2 do not play a significant role in hereditary prostate cancer. However, germline mutations in BRCA2 account for some cases of early-onset prostate cancer, although this is estimated to be less than 1% of early-onset prostate cancers in the United States.[20]
Prostate cancer aggressiveness inBRCAmutation carriers
The studies summarized in Table 9 used similar case-control methods to examine features of prostate cancer aggressiveness among men with prostate cancer found to harbor a BRCA1/BRCA2 mutation.
These studies suggest that prostate cancer in BRCA mutation carriers may be associated with features of aggressive disease, including higher Gleason score, higher prostate-specific antigen (PSA) level at diagnosis, and higher tumor stage and/or grade at diagnosis, a finding that warrants consideration as patients undergo cancer risk assessment and genetic counseling.
BRCA1/BRCA2and survival outcomes
Analyses of prostate cancer cases in families with known BRCA1 or BRCA2 mutations have been examined for survival. In an unadjusted analysis performed on a case series, median survival was 4 years in 183 men with prostate cancer with a BRCA2 mutation and 8 years in 119 men with a BRCA1 mutation. The study suggests that BRCA2 mutation carriers have a poorer survival than BRCA1 mutation carriers.[27] To further assess this observation, case-control studies were conducted (summarized in Table 10).
These findings suggest overall survival and prostate cancer–specific survival may be lower in mutation carriers than in controls.
Additional studies involving theBRCAregion
A genome-wide scan for hereditary prostate cancer using 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence of linkage to chromosome 17q markers.[28] The maximum logarithm of the odds (LOD) score in all families was 2.36, and the LOD score increased to 3.27 when only families with four or more confirmed affected men were analyzed. The linkage peak was centered over the BRCA1 gene. In follow-up, these investigators screened the entire BRCA1 gene for mutations using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers.[29] Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancers was found to have a truncating mutation (3829delT). The remainder of the individuals harbored one or more germline BRCA1 variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence of a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating mutations in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17–linked families.
In another study from the UM-PCGP, common genetic variation in BRCA1 was examined.[30] Conditional logistic regression analysis and family-based association tests were performed in 323 familial prostate cancer families and early-onset prostate cancer families, which included 817 men with and without prostate cancer, to investigate the association of single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kilobase region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (odds ratio [OR], 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.[28]
Mismatch Repair Genes
Four genes implicated in MMR, namely MLH1, MSH2, MSH6, and PMS2. Germline mutations in these four genes have been associated with Lynch syndrome, which manifests by cases of nonpolyposis colorectal cancer and a constellation of other cancers in families, including endometrial, ovarian, and duodenal cancers; and transitional cell cancers of the ureter and renal pelvis. Scattered case reports have suggested that prostate cancer may be observed in men harboring an MMR gene mutation.[31] The first quantitative study described nine cases of prostate cancer occurring in a population-based cohort of 106 Norwegian male MMR mutation carriers or obligate carriers.[32] The expected number of cases among these 106 men was 1.52 (P < .01); the men were younger at the time of diagnosis (60.4 years vs. 66.6 years, P = .006) and had more evidence of Gleason score of 8 to 10 (P < .00001) than the cases from the Norwegian Cancer Registry. Kaplan Meier analysis revealed that the cumulative risk of prostate cancer diagnosis by age 70 years was 30% in MMR gene mutation carriers and 8% in the general population. This finding awaits confirmation in additional populations. A population-based case-control study examined haplotype-tagging SNPs in three MMR genes (MLH1, MSH2, and PMS2). This study provided some evidence supporting the contribution of genetic variation in MLH1 and overall risk of prostate cancer.[33] To assess the contribution of prostate cancer as a feature of Lynch Syndrome, one study performed microsatellite instability (MSI) testing on prostate cancer tissue blocks from families enrolled in a prostate cancer family registry who also reported a history of colon cancer. Among 35 tissue blocks from 31 distinct families, two tumors from MMR mutation–positive families were found to be MSI-high. The authors conclude that MSI is rare in hereditary prostate cancer.[34]
Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[28] Fine-mapping of this region provided strong evidence of linkage (LOD score = 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger.[35] The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins).[36]Probands from four families were discovered to have a recurrent mutation (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the mutation. The mutation status was determined in 5,083 additional case subjects and 2,662 control subjects. Carrier frequencies and ORs for prostate cancer risk were as follows:
A validation study from the International Consortium of Prostate Cancer Genetics confirmed HOXB13 as a susceptibility gene for prostate cancer risk.[37] Within carrier families, the G84E mutation was more common among men with prostate cancer than among unaffected men (OR, 4.42; 95% CI, 2.56–7.64). The G84E mutation was also significantly overtransmitted from parents to affected offspring (P = 6.5 × 10-6).
Additional studies have emerged that better define the carrier frequency, prostate cancer risk, and penetrance associated with the HOXB13 G84E mutation. This mutation appears to be restricted to white men, primarily of European descent.[36,38,39] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases.[40] A pooled analysis that included 9,016 cases and 9,678 controls of European Americans found an overall G84E mutation frequency of 1.34% among cases and 0.28% among controls.[41]
Risk of prostate cancer by HOXB13 G84E mutation status has been reported to vary by age of onset, family history, and geographical region. A validation study in an independent cohort of 9,988 cases and 61,994 controls from six studies of men of European ancestry, including 4,537 cases and 54,444 controls from Iceland whose genotypes were largely imputed, reported an OR of 7.06 (95% CI, 4.62–10.78; P = 1.5 × 10?19) for prostate cancer risk by G84E carrier status.[42] A pooled analysis reported a prostate cancer OR of 4.86 (95% CI, 3.18–7.69; P = 3.48 × 10-17) in men with HOXB13 mutations compared with noncarriers; this increased to an OR of 8.41 (95% CI, 5.27–13.76; P = 2.72 ×10-22) among men diagnosed with prostate cancer at age 55 years or younger. The OR was 7.19 (95% CI, 4.55–11.67; P = 9.3 × 10-21) among men with a positive family history of prostate cancer and 3.09 (95% CI, 1.83–5.23; P = 6.26 × 10-6) among men with a negative family history of prostate cancer.[41] A meta-analysis that included 24,213 cases and 73,631 controls of European descent revealed an overall OR for prostate cancer by carrier status of 4.07 (95% CI, 3.05–5.45; P < .00001). Risk of prostate cancer varied by geographical region: United States (OR, 5.10; 95% CI, 3.21–8.10; P < .00001), Canada (OR, 5.80; 95% CI, 1.27–26.51; P = .02), Northern Europe (OR, 3.61; 95% CI, 2.81–4.64; P < .00001), and Western Europe (OR, 8.47; 95% CI, 3.68–19.48; P < .00001).[39] In addition, the association between the G84E mutation and prostate cancer risk was higher for early-onset cases (OR, 10.11; 95% CI, 5.97–17.12). There was no significant association with aggressive disease in the meta-analysis. One population-based, case-control study from the United States confirmed the association of the G84E mutation with prostate cancer (OR, 3.30; 95% CI, 1.21–8.96) and reported a suggestive association with aggressive disease.[43] In addition, one study identified no men of Ashkenazi Jewish ancestry who carried the G84E mutation.[44]
Penetrance estimates for prostate cancer development in HOXB13 G84E mutation carriers are also being reported. One study from Sweden estimated a 33% lifetime risk of prostate cancer among G84E carriers.[45] Another study from Australia reported age-specific cumulative risk of prostate cancer of up to 60% by age 80 years.[46]
HOXB13 plays a role in prostate cancer development and interacts with the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene identified to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility and implications for genetic counseling regarding the HOXB13 G84E mutation have yet to be defined.
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 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 of prostate cancer at the present time.
The Prostate Cancer Prevention Trial (PCPT; SWOG-9217), a prospective, randomized clinical trial of finasteride versus placebo, demonstrated a 25% reduction in prostate cancer prevalence 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]
The concern over the reported increase of high-grade prostate cancer in the finasteride arm compared with the placebo arm (6.6% of men analyzed vs. 5.1%, respectively, P = .005) in the original report from the PCPT was recently reanalyzed with consideration of possible biases that may have influenced these findings.[2] These biases included improved sensitivity of PSA and the digital rectal exam (DRE) for overall prostate cancer detection with finasteride, improved sensitivity of PSA for high-grade prostate cancer detection with finasteride, differences in participants reaching the study endpoints between the two arms, and increased detection of high-grade disease with finasteride due to reduction in size of the prostate gland. Using a bias-adjusted statistical modeling analysis, 7,966 participants in the finasteride arm and 8,024 participants in the placebo arm of the PCPT were studied. No statistically significant difference was found in the overall prevalence of high-grade prostate cancer with finasteride compared with placebo (4.8% vs. 4.2%, respectively, P = .12). Further analysis in a subset of men with a prostate cancer diagnosis who were treated with radical prostatectomy (n = 500) revealed that men on finasteride had less high-grade prostate cancer than men who took placebo (6.0% vs. 8.2%, respectively). The estimated risk reduction for high-grade prostate cancer from this subset analysis in men who had a prostatectomy and took finasteride was 27% (relative risk [RR], 0.73; 95% confidence interval [CI], 0.56–0.96; P = .02).[2]
Another study estimated the rate of true high-grade prostate cancer in the PCPT by extrapolating the Gleason score from the subset of participants who had undergone a radical prostatectomy.[3] Statistical modeling that accounted for misclassification of Gleason score from biopsy to radical prostatectomy was used in this study. When comparing the rates of true low-grade versus high-grade disease in the finasteride arm and the placebo arm, the estimated RR for low-grade and high-grade prostate cancer at prostatectomy was 0.61 (95% CI, 0.51–0.71) and 0.84 (95% CI, 0.68–1.05), respectively. Information was not reported as to whether men with a family history of prostate cancer had a reduction in high-grade prostate cancer in these analyses. Further definition of the prostate cancer prevention potential of finasteride in men with a family history of prostate cancer, along with genetic stratification to identify those men at truly increased risk of the disease, remain to be determined. Together these two studies suggest that the apparent excess risk of high-grade prostate cancer in men treated with finasteride may be explained by various biases not accounted for in the original analysis.
Level of Evidence: 1aii
(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.)
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.
Prostate-specific antigen and digital rectal exam
There is limited information about the efficacy of commonly available screening tests such as the 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.[4,5]
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 older than 40 years has been conducted.[6] 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 and 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 three were not confined to the prostate.[6]
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 two groups: sporadic (defined as only one first-degree relative with prostate cancer) or familial (with two or more cases of prostate cancer). PSA higher than 0.004 mg/L was present in 0.8% in men aged 40 to 49 years and in 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 ten prostate cancers detected in this study, nine were clinically localized and of intermediate Gleason scores (5–7).[7]
In a Finnish prostate cancer screening study, family history of prostate cancer was obtained in 2,099 prostate cancer patients.[5] This resulted in the identification of 103 prostate cancer families with two or more affected first-degree 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 seven (3.3%) subjects, including one at an advanced stage, and prostatic intraepithelial neoplasia in two (1%) subjects. 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.[8,9,10,11,12,13] These findings, however, may not be comparable to U.S. 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 above 3.0 mg/L (n = 1,261).[13] 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 mg/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.[13]
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 0.004 mg/L, 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 RR of developing prostate cancer among male relatives of men with prostate cancer was modest (RR, 1.3; 95% 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.[14]
Prostate cancer detection was analyzed in 609 high-risk men; 231 white men with a family history of prostate cancer; and 373 African American men, of whom approximately 30% had a family history of prostate cancer. Using aggressive biopsy criteria, 9.0% of the white men and 9.1% of the African American men were diagnosed with prostate cancer. Twenty-two percent of the prostate cancers diagnosed were Gleason score 7 or higher, and 20% of men diagnosed with prostate cancer had a prediagnosis PSA greater than 2.5 ng/mL. Further study is needed to define optimal screening measures in men with a family history of prostate cancer.[15]
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 not known.[16]
Current recommendations for screening at-risk members of familial or hereditary prostate cancer kindreds are based on expert opinion panels.[17] 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
Candidate prostate cancer biomarkers
Many new prostate cancer biomarkers (either alone or in combination) will be identified and proposed during the next 5 to 10 years. While this is an active area of research with a number of promising new biomarkers in early development, none of these biomarkers alone or in combination have been sufficiently well studied to justify their routine clinical use for screening purposes, either in the general population or in men at increased risk of prostate cancer based on family history.
Before addressing information related to emerging prostate cancer biomarkers, it is important to consider the several steps that are required to develop and, more importantly, to validate a new biomarker. One useful framework was described by the National Cancer Institute Early Detection Research Network investigators.[18] These authors indicated that the goal of a cancer-screening program is to detect tumors at an early stage so that treatment is likely to be successful. The gold standard by which such programs are judged is whether the death rate from the cancer for which screening is performed is reduced among those being tested. In addition, the screening test must be sufficiently noninvasive and inexpensive to allow widespread use. Maintaining high test specificity (i.e., few false-positive results) is essential for a population screening test because even a low false-positive rate results in many people having to undergo unnecessary and costly diagnostic procedures and psychological stress. It is likely that the use of several such cancer biomarkers in combination will be required for a screening test to be both sensitive and specific. Furthermore, a clinically useful test must have a high PPV (a parameter derived from sensitivity, specificity, and disease prevalence in the screened population). Practically speaking, a biomarker with a PPV of 10% implies that ten surgical procedures would be required to identify one case of prostate cancer; the remaining nine surgeries would represent false-positive test findings.[19] In general, the prostate cancer research community considers biomarkers with a PPV less than 10% to be clinically unacceptable. Finally, it is important to keep in mind that while novel biomarkers may be present in the sera of men with advanced prostate cancer (which comprise the vast majority of cases analyzed in the early phases of biomarker development), they may or may not be detectable in men with early-stage disease. This is essential if the screening test is to be clinically useful in the detection of localized and potentially curable prostate cancer.
It has been suggested that there are five general phases in biomarker development and validation:[18]
Phase I — Preclinical exploratory studies
Phase 2 — Clinical assay development for clinical disease
Phase 3 — Retrospective longitudinal repository studies
Phase 4 — Prospective screening studies
Phase 5 — Cancer control studies
Finally, for a validated biomarker test to be considered appropriate for use in a particular population, it must have been evaluated in that specific population without prior selection of known positives and negatives. In addition, the test must demonstrate clinical utility, that is, a positive net balance of benefits and risks associated with the application of the test. These may include improved health outcomes and net psychosocial and economic benefits.[20]
Prostate cancer poses a further challenge relative to the potential impact of false-positive test results. There are no reliable noninvasive diagnostic tests for early-stage disease, and the value of identifying early-onset disease has not been established. This is further complicated because prostate cancer is clinically heterogeneous, that is, a proportion of prostate cancer may be relatively indolent disease of uncertain clinical significance.[19] High test specificity (i.e., a very low false-positive rate) is required to avoid unnecessary screening and further diagnostic evaluation, which may include surgery.
New candidate prostate cancer single-nucleotide polymorphisms (SNPs) have been identified and studied individually, in combination with family history, or in various other permutations. Most of the study populations are relatively small and comprise highly-selected known prostate cancer cases and healthy controls of the type evaluated in early development phases I and II. Results have not been consistently replicated in multiple studies; presently, none are considered ready for widespread clinical application.
Multiplex assays
Because individual SNPs have not met the criteria for an effective risk assessment test, it has been suggested that testing multiple prostate cancer–related SNPs may be required to obtain satisfactory results. An initial study evaluated five chromosomal regions associated with prostate cancer in a Swedish population, three at 8q24, one at 17q12 and one at 17q24.3.[21] Sixteen SNPs within these regions were assessed in 2,893 men with prostate cancer and 1,781 controls. It was estimated that the five SNPs most strongly associated with prostate cancer accounted for 46% of prostate cancer in the Swedish men from this study. When considered independently, each SNP was associated with a small increase in prostate cancer risk. However, the investigators identified a cumulative stronger association with prostate cancer risk when multiple SNPs and family history were combined, versus men without any risk SNPs or a prostate cancer family history.[21]
A larger study of 5,628 men with prostate cancer and 3,514 controls from the United States and Sweden further strengthened this association.[22] For men carrying one or more risk SNPs, the estimated odds ratio (OR) ranged from 1.41 (95% CI, 1.20–1.67) for one SNP to as high as 3.80 (95% CI, 2.77–5.22) for four or more SNPs. The cumulative effect of family history with up to five SNPs was estimated to have an OR of 11.26 (95% CI, 4.74–24.75) for prostate cancer.[22] The observation that family history added significant strength to the SNP-related association suggests that there may be additional genetic risk variants yet to be discovered. All available data to date are derived from studies of sporadic prostate cancer. Familial prostate cancer has not been evaluated.
Nineteen SNPs identified as candidate prostate cancer risk variants in genome-wide association studies were studied in 2,893 prostate cancer cases and 1,781 controls from Sweden in an effort to identify a prostate cancer risk prediction model that did not include PSA.[23] The final model included the presence of any 11 risk factors selected among 22 risk alleles from the 11 significant SNPs and family history. Its sensitivity and specificity were 0.25 and 0.86, respectively; these results are similar to those obtained for PSA from the Prostate Cancer Prevention Trial (i.e., 0.21 and 0.94, respectively). PSA itself could not be analyzed in the current report. The authors suggest that future studies should combine PSA with their model, to determine if this combination further improves prostate cancer risk prediction.
This hypothesis was tested in another study that evaluated the clinical utility of five previously reported SNPs at 8q24, 17q12, and 17q24.3. This was a case-control study of white men in the United States comprising 1,308 cases and 1,266 age-matched controls without a self-reported history of prostate cancer.[24] The estimated OR for men carrying one SNP was 1.41 (95% CI, 1.02–1.97), which increased to an OR of 4.92 (95% CI, 1.58–18.53) for men carrying all five SNPs and having a first-degree relative with prostate cancer. However, in a subset analysis from this population, these five SNPs did not improve the ability to identify prostate cancer in cases relative to controls in this population when added to clinical variables that included age, PSA at diagnosis, or first-degree family history of prostate cancer (area under the curve [AUC] = 0.63 for clinical variables alone vs. AUC = 0.66 for clinical variables and five SNPs). There was also no improvement in predicting prostate cancer–specific mortality when these five SNPs were added to age at diagnosis, stage, Gleason score, PSA at diagnosis, first-degree family history of prostate cancer, and primary treatment. Therefore this SNP panel, while having replicated associations to prostate cancer risk, may have limited clinical utility.
Viewed in the context of the criteria previously described, this five-SNP assay would be classified as phase 2 in its development. While this appears to be a promising avenue of prostate cancer risk evaluation, additional validation is required, particularly in an unselected population representative of the clinical population of interest.
Level of Evidence: 3
Numerous research groups are attempting to overcome the limited clinical utility of multiple SNP panels relative to prostate cancer risk by significantly expanding the number of SNPs in their models. A report describing 22 prostate cancer risk factor variants in a single population found that various combinations of these markers yielded prostate cancer ORs greater than 2.5; however, these combinations occurred in only 1.3% of the population studied, illustrating how challenging it will be to find clinically useful SNP panels for this purpose.[25]
Efforts to elucidate the role of SNPs in identifying prostate cancer risk and the performance of SNPs in predicting prostate cancer development are in progress. One study reported that increasing numbers of SNPs identified from genome-wide association studies and family histories were able to discriminate men at twofold and threefold higher absolute risk of prostate cancer in a Swedish case-control study (cases = 2,899 and controls = 1,722).[26] For example, including family history and 28 SNPs in the analysis identified 18% of men with a twofold increased absolute risk of prostate cancer and 8% of men with a threefold increased risk. Notably, the SNPs in this study have not been associated with aggressive prostate cancer. These findings require further validation in longitudinal cohorts, diverse ethnic populations, and screening cohorts. This study suggests that adding more relatively common SNPs of low penetrance to a risk assessment panel may not achieve clinical utility.
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.[27,28,29,30] 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.[31]
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
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 Cancer Genetics Risk Assessment and Counseling for more information.) The components of genetic counseling include concepts of prostate cancer risk, 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 one in seven American men during their lifetime.[3] 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.[4,5] The proportion of prostate cancer associated with an inherited susceptibility may be even larger.[6,7,8] 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.[9] The three criteria include the following:
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.[10] They found that 90% of sons were interested in knowing whether there is an inherited susceptibility to prostate cancer and would be likely to undergo screening and 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 such as age, race, and dietary intake of fats and dairy products; documenting other medical problems; and evaluating genetics-related psychosocial issues.
Family history documentation is based on construction of a pedigree, and generally includes the following:
(Refer to the Documenting the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for a more detailed description of taking a family history.)
Analysis of the family history generally consists of four components:
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.[15] 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.[15] Self-reported family history of prostate cancer, however, may not be reliably reported over time,[16] 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, the following:
The most definitive risk factors for prostate cancer are age, race, and family history.[18] 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. (Refer to the Risk Factors for Prostate Cancer section of this summary for a more detailed description of prostate cancer risk factors.)
The psychosocial assessment in this context might include evaluation of the following:
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.[19]
Genetic Testing
At this time, with the exception of prostate cancer in a family with evidence of hereditary breast/ovarian cancer (HBOC) syndrome, clinical genetic testing to detect inherited prostate cancer predisposition is not available. (Refer to the BRCA1 and BRCA2 section of this summary and the PDQ summary on Genetics of Breast and Ovarian Cancer for more information about prostate cancer in HBOC.) None of the candidate susceptibility genes have been unequivocally associated with prostate cancer predisposition. 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.
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 Cancer Genetics Risk Assessment and Counseling for more information about psychological issues related to genetic counseling for cancer risk assessment.) When it becomes available, genetic testing for mutations in prostate cancer susceptibility genes 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 of prostate cancer is thought to be a factor influencing men's decisions to pursue prostate cancer screening and, possibly, genetic testing.[1] A study of 79 African American men (38 of whom had been diagnosed with prostate cancer and the remainder who were unaffected but at high risk of prostate cancer) completed a nine-item telephone questionnaire assessing knowledge about hereditary prostate cancer. On a scale of 0 to 9, with 9 representing a perfect score, scores ranged from 3.5 to 9 with a mean score of 6.34. The three questions relating to genetic testing were the questions most likely to be incorrect. In contrast, questions related to inheritance of prostate cancer risk were answered correctly by the majority of subjects.[2] Overall, knowledge of hereditary prostate cancer was low, especially concepts of genetic susceptibility, indicating a need for increased education. An emerging body of literature is now exploring risk perception for prostate cancer among men with and without a family history. Table 11 provides a summary of studies examining prostate cancer risk perception.
Study conclusions vary regarding whether first-degree relatives (FDRs) 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 as or less than that of the average man.[5,6] Other factors, including being married, have been associated with higher prostate cancer risk perception.[7] A confounder in prostate cancer risk perception was confusion between benign prostatic hyperplasia and prostate cancer.[3]
Anticipated Interest in Genetic Testing
A number of studies summarized in Table 12 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 the following:
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. Study participants expressed concerns about confidentiality of test results among employers, insurers, and family and stigmatization; potential loss of insurability; and the cost of the test.[8] These concerns are similar to those that have been reported in women contemplating genetic testing for breast cancer predisposition.[11,12,13,14,15,16] 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.[8]
Overall, these reports and a study that developed a conceptual model to look at factors associated with intention to undergo genetic testing [23] 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.[24,25]
Hereditary Prostate Cancer Families and Screening
The proportion of prostate cancers attributed to hereditary causes is estimated to be 5% to 10%,[26] and the risk of prostate cancer increases with the number of blood relatives with prostate cancer and young age at onset of prostate cancer within families.[27] There is considerable controversy in prostate cancer about the use of serum prostate-specific antigen (PSA) measurement and digital rectal exam 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 about prostate cancer in the general population and the Interventions section of this summary for more information about 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 FDRs 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.
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 13. In general, results appear contradictory regarding 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.
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 FDRs of prostate cancer patients expressed some concern about developing prostate cancer,[5] the level of anxiety reported is typically relatively low and is related to lifetime risk rather than short-term risk.[3,5] The concern is also higher in men who are younger than his FDR was at the time when their prostate cancer was diagnosed.[5] Unmarried FDRs worried more about developing prostate cancer than did married men.[5] Men with higher levels of concern about developing prostate cancer also had higher estimates of personal prostate cancer risk and had a larger number of relatives diagnosed with prostate cancer.[5] 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."[3]
Baseline distress levels: Among men who self-referred for free prostate cancer screening, general and prostate cancer–related distress did not differ significantly between men who were FDRs of prostate cancer patients and men who were not.[36] Men with a family history of prostate cancer in the study had higher levels of perceived risk. In a Swedish study, male FDRs 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 FDRs was at the 75th percentile. Depression was associated with higher levels of personal risk overestimation.[3]
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.[31] 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 age 50 to 60 years, having more than two 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 FDRs 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 FDRs of men with prostate cancer participating in a PSA screening study. One hundred twenty-eight FDRs 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.[37]
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.
Updated statistics with estimated new prostate cancer cases and deaths for 2014 (cited American Cancer Society as reference 1).
Updated statistics with age-specific probabilities of being diagnosed with prostate cancer in 2014.
Identifying Genes and Inherited Variants Associated with Prostate Cancer Risk
Revised text to state that because a man's lifetime risk of prostate cancer is one in seven, it is possible that families under study have men with both inherited and sporadic prostate cancer (cited American Cancer Society as reference 4).
Revised text to state that genome-wide searches have successfully identified susceptibility alleles for many complex diseases, including prostate cancer.
Revised text to state that to date, approximately 80 variants associated with prostate cancer have been identified by well-powered genome-wide association studies (GWAS) and validated in independent cohorts.
Added Eeles et al. as reference 187.
Added text to state that the association between risk and allele status for each variant listed in Table 4, Prostate Cancer Susceptibility Loci Identified Through GWAS in Men of European Ancestry, reached genome-wide statistical significance in more than one independent cohort.
Revised Table 4 to include an additional 40 variants that have been associated with prostate cancer.
Revised text to state that prostate cancer will affect an estimated one in seven American men during their lifetime (cited American Cancer Society as reference 3).
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Prostate Cancer are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Genetics of Prostate Cancer. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/genetics/prostate/HealthProfessional. Accessed <MM/DD/YYYY>.
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