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Genetics of Prostate Cancer (PDQ®) - National Cancer Institute

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Genetics of Prostate Cancer (PDQ®) - National Cancer Institute

National Cancer Institute at the National Institutes of Health


Risk Factors for Prostate Cancer
        Family history of prostate cancer
        Other potential modifiers of prostate cancer risk
Multiple Primaries
Risk of Other Cancers in Multiple-Case Families
Inheritance of Prostate Cancer Risk

 [Note: 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.]
 [Note: 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.[11-15] 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 affectedrelative.[13-17] 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]
Table 1. Relative Risk (RR) Related to Family History of Prostate Cancera
Risk Group RR for Prostate Cancer (95% CI) 
Brother(s) with prostate cancer diagnosed at any age3.14 (2.37–4.15)
Father with prostate cancer diagnosed at any age2.35 (2.02–2.72)
One affected FDR diagnosed at any age2.48 (2.25–2.74)
Affected FDRs diagnosed <65 y2.87 (2.21–3.74)
Affected FDRs diagnosed ≥65 y1.92 (1.49–2.47)
Second-degree relatives diagnosed at any age2.52 (0.99–6.46)
Two or more affected FDRs diagnosed at any age4.39 (2.61–7.39)

CI = confidence interval; FDR = first-degree relative.
aAdapted from Kiciński et al.[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 withBRCA1/BRCA2 mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[26-29] (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.[12,16,31-34] 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.[55-57]
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.[62-64] 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% fornoncarriers.[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 [65-68] 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]
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