Risk Factors for Prostate Cancer
Family History as a Risk Factor for Prostate Cancer
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.]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Many types of epidemiologic studies (case control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. An analysis of monozygotic and dizygotic twin pairs in Scandinavia concluded that 42% (CI, 29%–50%) of prostate cancer risk may be accounted for by heritable factors.[43] This is in agreement with a previous U.S. study that showed a concordance of 7.1% between dizygotic twin pairs compared with a 27% concordance between monozygotic twin pairs.[44] The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency of 0.003) autosomal dominant, highly penetrant allele(s).[21] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger).

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[45-47] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk for carriers was estimated to be 89% by age 85 years compared with 3.9% for noncarriers.[44] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in first-degree relatives of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there may be multiple genes associated with prostate cancer [48-51] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (<66 years) compared with noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[52]

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