Family history of prostate cancer and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study†
Article first published online: 10 JUN 2008
Published 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 123, Issue 5, pages 1154–1159, 1 September 2008
How to Cite
Ahn, J., Moslehi, R., Weinstein, S. J., Snyder, K., Virtamo, J. and Albanes, D. (2008), Family history of prostate cancer and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Int. J. Cancer, 123: 1154–1159. doi: 10.1002/ijc.23591
This article is a US Government work and, as such, is in the public domain in the United States of America.
- Issue published online: 17 JUN 2008
- Article first published online: 10 JUN 2008
- Manuscript Accepted: 5 MAR 2008
- Manuscript Received: 19 OCT 2007
- Department of Health and Human Services (Public Health Service). Grant Numbers: N01-CN-45165, N01-RC-45035, N01-RC-37004
- Intramural Research Program of the National Institutes of Health
- Division of Cancer Epidemiology and Genetics
- National Cancer Institute
- family history;
- prostate cancer;
Prostate cancer family history has been associated with increased risk of the malignancy. Most prior studies have been retrospective and subject to recall bias, however, and data evaluating interactions with other important risk factors are limited. We examined the relationship between a family history of prostate cancer and prostate cancer risk in relation to body size, micronutrients and other exposures in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of Finnish male smokers. Family history of cancer information was self-reported once during the study in 1991, and anthropometry was measured by trained personnel. Among 19,652 men with complete data, 1,111 incident cases were identified during up to 12.3 years of follow-up. A first-degree family history of prostate cancer was associated with an overall relative risk (RR) of 1.91 (95% CI = 1.49–2.47) and a RR of 4.16 (95% CI = 2.67–6.49) for advanced disease (stage ≥ 3), adjusted for age and trial intervention. Our data also suggest that to some degree, height, body mass index, and serum α-tocopherol and β-carotene modify the family history and prostate cancer association, although the interactions were not statistically significant. Supplementation with vitamin E or β-carotene did not modify the family history-prostate cancer association. This study provides additional evidence that family history is a significant risk factor for prostate cancer. Published 2008 Wiley-Liss, Inc.
Prostate cancer is the most common non-skin cancer and the second leading cause of cancer death among men in the United States.1 Although little is known about the underlying causes of prostate cancer, family history of the disease has been consistently associated with increased risk. A recent meta-analysis estimated that a family history of prostate cancer in first-degree relatives was associated with a relative risk of 2.5 [3.5 for risk of early onset (<60 years old) disease].2 However, most existing studies are limited to retrospective case-control studies3–7 and some existing cohort studies are based on family history probands.8–10 Additionally, 2 prospective studies reported that associations between body mass index and prostate cancer were more pronounced among men with a positive family history,11, 12 but data evaluating interactions with other important prostate cancer risk factors are limited.
Family history is an important public health screening tool for identification of high-risk groups, particularly in the post-genomic era with the discovery of inherited causes of many diseases including cancers.13 Since prostate cancer is a result of complex genetic and environmental interactions,14 family history can be a personalized genomic tool that captures many of these interactions13 and is essential to individualized cancer prevention strategies. Thus, accurate risk assessment of a family history as well as evaluation of interaction with known or potential risk factors of prostate cancers are particularly important and merit investigation using multiple study designs.
In this paper, we hypothesized that a family history of prostate cancer in first-degree relatives may predispose men to prostate cancer and may enhance risk conferred by other known or potential prostate cancer risk factors. Using a prospective design, we investigated the association of family history, assessed once during the study in 1991, with prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. We also assessed the modifying influences of known or potential prostate cancer risk factors on risk relationships between family history and prostate cancer risk.
Material and methods
The ATBC Study was a placebo-controlled, double-blinded primary prevention trial with a 2 × 2 factorial design that tested the hypothesis of whether α-tocopherol or β-carotene supplementation would reduce the incidence of lung or other cancers in male smokers. Study rationale, design, and methods have been previously described.15 Between 1985 and 1988, 29,133 eligible men aged 50–69 years in southwestern Finland who smoked at least 5 cigarettes per day were randomized to receive supplements (50 mg/day of α-tocopheryl acetate, 20 mg/day of β-carotene or both) or a placebo. Criteria for exclusion from the study included a history of malignancy other than nonmelanoma cancer of the skin or carcinoma in situ, severe angina upon exertion, chronic renal insufficiency, liver cirrhosis, chronic alcoholism, receipt of anticoagulant therapy, other medical problems which might limit long-term participation, and current use of supplements containing vitamin E (>20 mg/day), vitamin A (>20,000 IU/day), or β-carotene (>6 mg/day). The trial ended on April 30, 1993, and follow-up continued after randomization for the present study until death or through April 30, 2003. The study was approved by the institutional review boards of both the U.S. National Cancer Institute and the Finnish National Public Health Institute. All study participants provided written informed consent prior to the study's initiation.
Nearly all cases were ascertained by Finish Cancer Registry during the study follow-up, with additional centralized record reviews through April 1999. These reviews and other data provided strong support for the robustness of the Finnish Cancer Registry data regarding our cohort.16 By design for the postintervention analysis,17 the medical records of each prostate cancer case diagnosed through April 1999 were centrally reviewed by 2 study oncologists to confirm the diagnosis and stage. In addition, the histopathologic and cytologic specimens of the cases were reviewed by study pathologists during the trial and post-trial periods (56% of total cases). Prostate cancer cases diagnosed after April 1999 had only Finnish Cancer Registry confirmation of the diagnosis, histology, and diagnosis date. Stage of prostate cancer as defined by the American Joint Committee on Cancer 199218 was available for cases diagnosed through April 1999 (n = 571). Stage III and IV cases were considered advanced disease.
At their baseline visit, the study participants completed baseline questionnaires on general background characteristics including medical, smoking, and lifestyle histories. Trained study staff using standard methods measured height and weight. Body mass index (BMI) was calculated from measured height and weight (kg/m2). Physical activity was categorized based on combined occupational and leisure time activity with those sedentary in both activity types serving as the lowest level. Fasting blood samples were collected and stored at −70°C, and serum α-tocopherol, β-carotene, and retinol concentrations were determined by reverse-phase high-performance liquid chromatography, as described previously.19 The between-run coefficients of variation were 2.2 for α-tocopherol, 3.6% for β-carotene, and 2.4 for retinol. Family history was assessed by a self-administered questionnaire completed in 1991 with detailed information queried for diagnoses of 9 common cancers (i.e., prostate, breast, lung, colon, rectal, bladder, stomach, pancreas, skin, and other cancers) among parents and siblings. Participants were also specifically asked how many brothers and sisters they had.
Person-time was calculated from the return date of the family history questionnaire (1991) to the date of prostate cancer diagnosis, death, or April 30, 2003, whichever came first. Only subjects with complete data were included in the analyses. Participants were ineligible for this study of family history if they did not complete the family history questionnaire (n = 8,257), food frequency questionnaire (FFQ; n = 1,149) or serum vitamin measurements (n = 21). After exclusions, the analytic cohort consisted of 19,652 men with 1,111 cases. There were no significant differences in prostate cancer risk factors between the whole ATBC cohort and the analytic cohort for this study of family history (data not shown). For example, the prostate cancer risk increase per 1 year of age were 1.09 (95% CI = 1.08–1.11) and 1.09 % (95% CI = 1.08–1.10) for the whole and analytical cohorts, respectively.
Age-adjusted baseline descriptive characteristics of participants were calculated using general linear models (GLM), and p-values for the difference by family history status were also calculated. Relative risks (RR) and 95% confidence intervals (95% CI) were determined using Cox proportional hazards models. All multivariable models were adjusted for age at randomization (continuous) and trial intervention (α-tocopherol and β-carotene supplement, yes/no). Factors that did not confound the family history associations included the following: number of brothers, BMI (<25, 25.0–29.9, 30+, kg/m2), height (tertile), benign prostatic hyperplasia (yes/no), intakes of total energy (continuous), carbohydrate, protein, fat, linoleic acids, meat, total vitamin E and β-carotene (diet and supplement), lycopene, and alcohol, number of cigarettes smoked per day, number of years of smoking, physical activity (low, medium, high), urban residence (yes/no), education (elementary school higher/not higher), and marital status (yes/no). When those variables were added to individual models in a stepwise fashion, each factor produced a nonsignificant, less than 10% change in family history relative risk.
To evaluate the joint effects of family history and known and potential prostate cancer risk factors, variables reflecting the combined exposures were analyzed using a common referent category (e.g., no family history combined with the lowest category of the risk factors tested). Tertiles of anthropometry, diet and lifestyle variables were created. To test multiplicative interactions, cross-product terms were added to a fully-adjusted model. Absolute rates of prostate cancer were standardized to the age distribution of person-years experienced by all study participants, using 5-year age categories. All statistical analyses were performed using SAS software (SAS Institute, Cary, North Carolina), and statistical tests were 2-sided.
The mean age at baseline of the study participants was 56.9 years (median 56, range 49–70 years). Age-adjusted characteristics of the study participants by prostate cancer family history status are shown in the Table I. Five hundred eighty-seven men, or 3.0%, had a family history of prostate cancer in first-degree relatives (i.e., father or brother). Men with a family history were slightly older, taller, and more educated, compared with men with no family history. The number of brothers was lower among those with no family history of prostate cancer. In addition, men with a family history had higher average serum retinol and a higher prevalence of benign prostatic hyperplasia. However, variables which may be related to health-conscious behavior, such as physical activity and alcohol consumption, did not significantly differ by family history status.
|Characteristics12||Family history of prostate cancer (mean ± SD)|
|No (N = 19,065, 97%)||Yes (N = 587, 3%)||p-value|
|Age, years||56.9 ± 4.95||57.3 ± 5.06||0.03|
|Number of brothers||1.8 ± 1.8||2.2 ± 1.8||<0.0001|
|Number of sisters||1.7 ± 1.7||1.9 ± 1.7||0.29|
|Height, cm||173.8 ± 6.1||174.7 ± 6.1||0.001|
|Weight, kg||79.6 ± 12.5||80.0 ± 12.5||0.41|
|Body mass index, kg/m2||26.3 ± 3.7||26.2 ± 3.7||0.47|
|Daily dietary intake|
|Total energy, kcal||2825.8 ± 773.1||2810.2 ± 795.1||0.45|
|Carbohydrate, g||307.5 ± 42.8||306.1 ± 42.8||0.38|
|Protein, g||103.6 ± 13.6||104.3 ± 13.6||0.28|
|Saturated fat, g||52.7 ± 13.3||52.9 ± 13.3||0.73|
|Linoleic acid, g||9.4 ± 6.0||9.4 ± 6.0||0.99|
|Total vitamin E, mg||14.6 ± 15.8||15.2 ± 15.9||0.39|
|α –tocopherol, mg||10.5 ± 4.3||10.5 ± 4.3||0.78|
|Lycopene, μg||820.5 ± 719.1||824.2 ± 719.2||0.99|
|Selenium, μg||90.0 ± 15.2||90.8 ± 15.2||0.24|
|Vitamin C, mg||100.5 ± 42.8||99.2 ± 42.8||0.49|
|Biomarker serum concentration|
|α –tocopherol, mg/L||12.1 ± 2.8||12.0 ± 2.8||0.73|
|β-carotene, μg/L||222.5 ± 190.7||222.4 ± 190.9||0.86|
|Retinol, μg/L||589.9 ± 122.6||604.8 ± 122.8||0.003|
|Total cholesterol, mmol/L||6.3 ± 1.15||6.2 ± 1.09||0.32|
|HDL cholesterol, mmol/L||1.2 ± 0.30||1.2 ± 0.30||0.90|
|Alcohol use, g||17.0 ± 19.6||16.7 ± 19.6||0.69|
|Numbers of cigarette/day||20.2 ± 8.6||20.0 ± 8.6||0.79|
|Vitamin supplement use, %||23.3||24.9||0.18|
|Urban residence, %||41.5||39.2||0.27|
|Education, %> elementary school||23.6||28.4||0.001|
|Benign prostatic hyperplasia, %||3.8||5.7||0.01|
|Physical activity, % low3||13.3||12.7||0.61|
|Physical activity, % medium3||54.9||57.4|
|Physical activity, % high3||32.0||29.9|
|Intervention, % AT supplement||50.0||52.2||0.29|
|Intervention, % BC supplement||49.5||52.1||0.23|
Among 19,652 men with complete data, 1,111 incident prostate cancer cases were identified during the follow-up period. Age at diagnosis was somewhat earlier among men with a family history of prostate cancer, compared with men with no family history, although distributions of age at diagnosis and time to diagnosis did not statistically differ by family history status (Table II). Men with a family history were more likely to have advanced disease (58% for men with family history versus 31% for men without family history; p = 0.0005). However, the method of diagnosis and percent receiving oncological reviews did not differ by family history.
|No family history (N = 1,048) (%)||Family history (N = 63)||p-value|
|Age at diagnosis|
|≤60 years||33 (3.2)||3 (4.7)||0.89|
|61–65 years||203 (19.4)||13 (20.6)|
|66–70 years||336 (32.2)||20 (37.8)|
|71+ years||476 (45.4)||27 (42.9)|
|Time to diagnosis|
|0–5 years||281 (26.8)||16 (25.4)||0.09|
|6–10 years||504 (48.1)||37 (58.7)|
|11–15 years||263 (25.0)||10 (15.9)|
|Method of diagnosis (n, %)1|
|Histology||522 (94.2)||35 (84.6)||0.09|
|Cytology||30 (5.4)||5 (12.8)|
|Clinical||2 (0.4)||1 (2.6)|
|Tumor grade (n, %)1||0.27|
|Well differentiated||128 (23.8)||9 (25.7)|
|Moderately differentiated||283 (52.6)||14 (40.0)|
|Poorly differentiated||127 (23.6)||12 (34.3)|
|TNM Stage at diagnosis (n, %)1|
|0–II||380 (69.3)||16 (42.1)||0.001|
|III||71 (12.8)||13 (34.2)|
|IV||99 (17.9)||9 (23.7)|
|Advanced disease2||170 (30.7)||22 (57.9)||0.0005|
A family history of prostate cancer in first-degree relatives was associated with a nearly doubling of prostate cancer risk (Table III). Adjustment for number of brothers, height, serum retinol, education, benign prostatic hyperplasia, red meat intake, and lycopene intake did not alter the risk estimates (data not shown). We had conducted a sensitively analysis that used the full 19 years of follow-up from original study entry, which yielded RR (95% CI) = 1.91(1.49–2.47) for analytic cohort and RR 1.90 (1.48–2.46) for the whole cohort. Men whose fathers had been diagnosed with prostate cancer showed a slightly greater risk increase (RR = 1.99) and men who had brother(s) with the disease had a slightly smaller risk increase (RR = 1.70) compared with those with no family history. For cases with early onset of disease (i.e., < 65 years), family history of prostate cancer was associated with a RR of 2.40, based on 16 and 236 cases with and without family history, respectively. By contrast, for cases with later onset disease, the RR associated with family history was 1.81 (95% CI 1.34–2.43). Because most men with a family history of prostate cancer in our cohort had either a father or only 1 brother affected with only 5 cases having more than one primary relative affected, we were not able to evaluate whether having additional first-degree relatives conferred even higher risk. Men with a family history of prostate cancer had over 4 times the risk of advanced prostate cancer compared with men with a negative family history (Table III). A tangential evaluation of the possible role of shared environments in the prostate cancer family history assessment showed that positive family histories of other common cancers (i.e., breast, lung, or colorectal cancer) were not associated with increased prostate cancer risks. Family history of other cancers was not associated with prostate cancer risk (data not shown).
|Family history of cancers||Total prostate cancer cases (N = 1,111)||Advanced prostate cases only (N = 192)|
|Cases||RR1||95% CI||Cases||RR1||95% CI|
|No family history||1,048||1.00||182||1.00|
|Father or brother(s)||63||1.91||1.49–2.47||24||4.16||2.67–6.49|
|No family history||900||1.00||162||1.00|
|Mother or sister(s)||86||1.16||0.93–1.48||16||1.21||0.73–2.06|
|No family history||879||1.00||156||1.00|
|Any first-degree relative||108||0.97||0.80–1.19||16||0.79||0.48–1.31|
|No family history||949||1.00||164||1.00|
|Any first-degree relative||31||1.09||0.82–1.46||4||0.93||0.49–2.03|
Risks associated with a first degree of family history were somewhat more pronounced among taller, heavier, and more active men, as well as those with lower serum α-tocopherol and higher β-carotene and retinol concentrations (Table IV); however, these interactions were not statistically significant. There was a suggestion that at low serum β-carotene levels, family history increased prostate cancer risk, little if at all, whereas at higher levels the risk was double (p interaction=0.08). α-Tocopherol and β-carotene supplementation intervention did not modify the family history-prostate cancer association, although it appeared stronger in the α-tocopherol study arm. These same characteristics showed no association with prostate risk among men with no family history, and weak to moderate positive associations among men having a family history (with the exception of an inverse association for serum alpha-tocopherol in this group). We were not able to evaluate interactions for advanced disease given the sample size, since the number of advanced cases was limited.
|No family history||Family history||p interaction|
|Cases||Incidence rate1||RR2||95% CI||Cases||Incidence rate1||RR2||95% CI|
|Serum α-tocopherol (mg/L)5|
|Serum β-carotene (ug/L)5|
|Serum retinol (ug/L)5|
|α-tocopherol (50 mg/day)|
|β-carotene (20 mg/day)||0.80|
In this large prospective cohort study, with a long follow-up period, having a family history of prostate cancer in first-degree relatives was associated with a nearly doubling of risk for incident prostate cancer and of early onset disease (<65 years) in particular. In addition, men with a positive family history were over 4 times more likely to have an advanced disease when diagnosed. Our data also suggest that to some degree, height, serum α-tocopherol and β-carotene may modify the family history–prostate cancer association. The study provides additional prospective evidence and quantitative details regarding family history as a significant risk factor for prostate cancer.
Although the family history–prostate cancer association is fairly established, few of the prior studies have been prospective, which raises the issue of recall bias and its impact on the magnitude of the previously observed associations. Our risk estimates are very similar to registry-based, prospective investigations of incident prostate cancer in Sweden (RR = 1.65)20 and the Netherlands (RR = 1.77),21 as well as to prostate cancer mortality in the American Cancer Society Cancer Prevention Study II cohort (RR = 1.6).22 These risk estimates are substantially lower than those from case–control studies, which ascertained data on family history retrospectively and may have overestimated risk.23–27 Given that family history reflects not only shared genes but also shared environments and common behaviors,14 lower risk estimates could in part result from less variability in the latter factors, particularly in a relatively homogeneous population such as in the present study. In this regard, it is interesting to note that having a family history of other cancers that do share some of the same risk factors with prostate cancer (i.e., red meat consumption with colorectal cancer)28, 29 was not associated with prostate cancer risk in our study, although 1 study reported that family history of breast cancer was associated with a prostate cancer relative risk of 1.7.30
Although it has been thought that 5–10% of prostate cancer is accounted for by genetic susceptibility,31 an analysis of monozygotic and dizygotic twin pairs in Scandinavia concluded that 42% (95% CI, 29–50%) of prostate cancer risk may be heritable.32 More recently, linkage analysis combined with genome-wide scan data from 1,233 families identified 5 suggestive regions (i.e., 5q12, 8p21, 15q11, 17q21 and 22q12),33 with significant linkage at 22q12 (logarithm of the odds score = 3.57) as well as 8q24.34 Suggestive linkage was also observed at 1q25, 8q13, 13q14, 16p13 and 17q21, among 269 families with at least 5 affected members. Although high penetrance germline mutations have not been established for prostate cancer (as, e.g., with BRCA1 and BRCA2 and breast cancer), data from such pedigree and genome-wide scan studies may lead to identification of loci underlying genetic susceptibility and prioritization of chromosomal regions for further study.
Several2, 21, 30, 35 but not all,22 studies have found that a history of prostate cancer in a sibling confers greater risk than that of paternal history, which would be consistent with the additional contribution to risk of a shared environment in childhood and adolescence. We observed a somewhat stronger association with paternal history, although the number of cases was small, and the confidence intervals for paternal versus sibling history were not mutually exclusive. Since we queried family history only once during the study, history of prostate cancer among brothers may not have been fully manifested, as compared with that for fathers. This probably influenced our risk estimates for the sibling history.
Although the interactions evaluated were not statistically significant in our study, risk associated with family history was somewhat pronounced among taller and overweight men, a finding supported by other studies of heredity-anthropometry interactions. For example, Sellers and colleagues36 reported that the increased risks of breast cancer associated with a high waist-to-hip ratio, low parity, and greater age at first birth were more pronounced among women with a family history of breast cancer. In line with the present findings, Rohrmann et al.12 reported stronger positive BMI-prostate cancer associations among men with younger age at onset of the disease. By contrast, Giovannucci et al.11 reported a stronger and significant inverse association between BMI and prostate cancer among men with a family history and for early disease onset (i.e., before 60 years of age) and suggested that this might be due to lower androgen status in obese men and a higher ratio of sporadic to hereditary cases among them. These data indicate that the development of prostate cancer may differ between men with and without a hereditary predisposition to the disease.
We observed the modest (nonsignificant) physical activity effect modification, suggesting little or no activity impact among men with no family history and a small, nonsignificant risk increase in those with an FDR, although the role of activity in prostate cancer is not clear. Findings could be due to chance, and further studies are warranted. To our knowledge, ours is the first prospective study to examine the modifying influences of serum micronutrients on the association between family history and prostate cancer risk. How serum α-tocopherol, β-carotene, or retinol might modify the risk associated with family history is not clear, particularly when α-tocopherol and β-carotene supplementation did not. Even though these interactions were not formally significant, other studies of family history and prostate cancer risk in relation to these serum micronutrients would be informative.
Our investigation benefits from its prospective nature and approximately 100% cancer ascertainment for the cohort but also has some limitations. Assessment of family history was based on self-report (as in most previous studies), and validation of reported cancers through the cancer registry or family members was not feasible. The prevalence of family history of prostate cancer we observed (3%) was, however, similar to that in the Dutch cohort (3.0%),21 and only slightly lower than in the U.S. (4.6%)30 and Swedish cohorts (6.4%)20 (although the latter encompassed 30 years of registry follow-up). Underreporting of prostate cancer family history is possible (sensitivity, 70% and specificity, 94%37), though it is unlikely to differ by prostate cancer status since it was ascertained years before diagnosis. Such nondifferential misclassification would be expected to attenuate the risk estimates toward the null, with the true risk estimates being larger than those observed.38 Because family history information was collected only once during the study and because participants are relatively young age for the group at entry, it is also possible that additional family members (particularly brothers) were diagnosed with prostate cancers during the subsequent 12 years of follow-up, with a resulting underestimation of the prevalence of family history. Nonetheless, the incomplete ascertainment of FDRs should in large part be nondifferential with respect to prostate cancer status. Detection bias resulting from more vigilant screening also appears unlikely, however, because men with a prostate family history did have higher disease stage at diagnosis than men with no family history, which is consistent with findings regarding breast cancer.39 Information on Gleason score was available from only a small number of the cases diagnosed during the original ATBC Study trial period (n = 320), and thus our advanced disease definition was based on stage information. Finally, since this study was based on smokers, our results may not be generalizable to nonsmoking populations.
In summary, this prospective study of Finnish men having up to 12 years of follow-up provides additional prospective evidence that having a family history of prostate cancer is a significant risk factor for developing the disease, with a doubling of risk overall (quadrupling of risk for advanced disease). Possible interactions between family history and body size and serum antioxidant vitamins were also suggested and should be reevaluated in other studies. Based on the increased risk resulting from family history, recommendations for early detection practices are advocated by, for example, the American Cancer Society Cancer Detection Guidelines, the Centers for Disease Control and Prevention, and the National Cancer Institute.
- 1American Cancer Society. Cancer facts and figures 2006. Atlanta, GA: American Cancer Society, 2006.
- 18AJCC. Cancer staging manual. Philadelphia: Lippincott-Raven, 1997.
- 38Epidemiologic research. New York, NY: Van Nostrand Reinhold Company, 1982., , .