This study found increased risks of PCa for men with a family history of PCa (RRs=1.78–2.34), which was consistent with the risk estimated in previous meta-analyses (2–2.5) (14
). The risk of PCa has been found to increase with the number of relatives affected by PCa (12
), which was consistent with our findings. A family history of PCa and younger onset age among relatives were significantly associated with the risk of PCa, which was consistent with previous studies (7
). Some studies found that PCa risk was higher among men with an affected brother than among those with an affected father (9
), but this was not evident in the present study [brother(s): 1.84 vs. father: 1.78] or in others (13
). Regarding BCa family history and PCa risk, our finding suggests that X-linked or recessive mode of inheritance may not be the major mode of conferring family history of PCa risk (33
). The combination of PCa and BCa family history (RR=1.51) did not increased the risk of PCa further than only one of the family histories (1.71 and 1.30 for family history of PCa and BCa, respectively), and the magnitude of PCa risk was not as high as in a previous study (RR=5.8) (9
). Although PSA screening was related to identification of occult prostate cancer (15
), exclusion of healthy men without a PSA test only slightly weakened the association. In addition, disease aggressiveness and tumor grade were not related to the risk of PCa when we compared men with PCa family history with those without. However, a positive BCa family history was significantly associated with an elevated the risk of non-aggressive or low-grade PCa.
We also observed that having a female family member(s) (especially a mother) with BCa was related to increased PCa risk (RR=1.24), which was consistent with one of the previous studies (RR=1.34) (13
) but not another study (28
). However, mortality, instead of incidence, was the outcome of the study with the significant finding (13
), and therefore the endpoints are not directly comparable. One study found the risk of PCa significantly elevated (RR=2.7) when a mother had a positive family history of BCa and/or ovarian cancer (9
). However, in that study (9
), we are unable to dissect whether the risk of PCa resulted from the family history of BCa or ovarian cancer. The biological mechanism relating the mother’s BCa family history to PCa risk has also not been investigated, and a role of BRCA1
was speculative (34
). However, results from the whole-genome association study of Cancer Genetic Markers of Susceptibility, National Cancer Institute (https://caintegrator.nci.nih.gov/cgems/aboutSetup.do
) did not support the association between SNPs in the BRCA2
gene and the risk of PCa. Another possibility was that the inclusion of sib sets without any girls resulted in a null association between a sister’s history of BCa and the risk of PCa. While statistically significant, the association with BCa was much weaker than that of family history of PCa.
Familial PCa tends to be diagnosed at a younger age than sporadic PCa (36
). This study lends credence to that finding, because we found that men with a family history of PCa had a higher risk of early-onset PCa than those without a family history of PCa. As in previous studies (12
), we found that the risk of PCa was higher in men whose relatives were diagnosed with PCa when they were <60 years old (). We also observed that, a family history of PCa was equally related to aggressive and non-aggressive PCa (), which conflicted with previous findings (13
). Similarly, men with a family history of PCa had a significantly higher risk of PCa than men without a family history of the disease, regardless of tumor grade. Therefore, we did not confirm the findings from previous studies (2
) that men with a family history of PCa were less likely to have high-grade disease. However, the family history of BCa was only significantly associated with the risk of non-aggressive or low-grade PCa, although our power for aggressive PCa was limited; this association has not been reported previously.
In the United States, PSA screening started in the early 1990s and has led to more frequent identification of PCa in its early stages. PCa family history (15
), higher educational level (40
), and older age (41
) are associated with frequency of undergoing PSA screening and thus could bias the study results. No study has explored the effect of PSA screening on the association between family history and the risk of PCa. In our study, a higher proportion of men with a PCa or BCa family history than men without a family history had a PSA screening [PCa family history (yes vs. no): 92% vs. 84%; BCa family history (yes vs. no): 95% vs. 92%, ]. About 8% of men with a positive PCa family history had elevated PSA levels, which was consistent with a previous study in asymptomatic men from families at high risk for PCa in a Finnish population (10%) (15
). When we conducted an analysis that excluded healthy men without PSA screening, our findings did not change appreciably. In addition, family history status did not affect the propensity for diagnostic tests. For example, on the 1994 questionnaire, we had asked men if they ever had an elevated PSA test and a prostate biopsy; among men with an elevated PSA level, the likelihood of having had a biopsy did not vary by family history status: 70% vs. 72% for men with a family history of PCa vs. without, and 73% vs. 71% for men with a family history of BCa vs. without. Thus, our findings suggest that detection bias did not appreciably affect our results.
A strength of this study is that it is one of the largest to date (3,695 PCa cases) and is of prospective design, which avoids recall bias and allows the assessment of PCa risk by age at onset in both the family members and the “proband.” Family history data were available in 87–97% of participants and were updated over time for family history of PCa. Although family history of PCa was self-reported, previous studies found such data to be highly accurate (86.2% in a US population (42
) and 92% in a Swedish population) (43
). Our participants are health professionals and likely report family history accurately. PSA screening has changed the epidemiologic patterns of diagnosed PCa (e.g., average age, incidence, proportion that are aggressive), but most studies were not conducted in the PSA era. Disease aggressiveness is available with a relatively large number of events in the aggressive category to obtain stable risk estimates. In addition, fewer studies have been able to assess the association with a family history of BCa, so this study adds additional important data to the literature.
However, our study had some limitations. We did not have complete data on age at diagnosis of PCa or BCa among relatives. PCa and BCa are diseases with a relatively late onset, and some siblings of the study participants may have been too young to develop the disease during follow-up. In addition, the incidence of PCa is higher among African Americans than among whites (19
), and African Americans reported a family history of PCa more often than did whites (18
) and were younger at PCa diagnosis (18
). However, this study had limited power to test our hypothesis for groups other than whites. Because this study was composed of a highly PSA screened population (cumulative percentage between 1994 and 2004>84%), the results should be generalized to similar populations.
Individuals from the same family share part of their genetic makeup and some of their environmental exposures (e.g., diet, carcinogens, socioeconomic status, and lifestyle) during part of their lives. Except for a common variant found in 3 case-control series of European ancestry (44
), no other major susceptibility genes for PCa have been consistently found across populations. We found that a positive PCa family history was related to early-onset PCa, with associations similar for a paternal or fraternal history. In addition, BCa family history in a mother or a sister was significantly but modestly associated with PCa. There was not an appreciable difference according to stage or grade of the disease according to PCa family history, but BCa family history was associated with increased risk of non-aggressive or low-grade PCa. Exclusion of healthy men without PSA screening did not change our findings, and family history of PCa and BCa was unlikely to alter the likelihood of a man with an elevated PSA undergoing biopsy. These findings may provide important information for primary care providers and urologists. Further study is warranted to identify potential mechanisms and modifiers of these associations.