Family History as a Risk Factor for Prostate Cancer
As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[30,31,32,33,34] 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.[31,35,36] 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.[32,33,34,35,36] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.
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 RR of 3.3 (95% CI, 1.8–5.9) for prostate cancer among men with a family history of the disease. 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).
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 (FDR) and 5.1 (95% CI, 3.3–7.8) for two or more FDRs, 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.
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. 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 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. 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 familial history of the disease.