Abstract
Background/Aim: Vitamin D deficiency in African-Americans is common due to the high melanin content of the skin that reduces the absorption of UV radiation. To determine if there is a correlation between UV exposure, tanning potential and vitamin D with prostate cancer (PC) risk, we conducted a case–control study of 183 African-American men aged 40 years and older residing in the Washington, DC area. Patients and Methods: PC status was described as a binary variable as the presence or absence of cancer and the environmental factors as continuous variables. We used a logistic regression model describing PC as the response, while age, tanning potential, sunlight and vitamin D were treated as the predictors. Results: Men aged 60 years and older had a seven-fold increased risk for developing PC compared to those aged 50 years and less (p<0.003). Tanning potential was a significant (p=0.05) risk factor for PC, while sunlight exposure and vitamin D were not. Tanning potential was also significant (p=0.044) when adjusted for vitamin D and age. However, tanning potential was only marginally significant when adjusted for sunlight exposure (p=0.064) Conclusion: The findings of this study indicate that tanning potential may be a predictor for PC risk in African-American men.
Prostate cancer is the second leading cause of cancer-related deaths among men in the United States (1). Men of African-American descent are at a significantly higher risk of developing prostate cancer and dying from it than Caucasian men (2-4). African-American men also appear to be more commonly diagnosed with this disease at an advanced stage, with aggressive histology and increased cancer-related mortality (5-7).
There is accumulating evidence that vitamin D may play an important role in the occurrence and progression of prostate cancer (8-11). Vitamin D deficiency is widespread throughout the United States (12) and the world (13-16). Researchers have suggested that the high incidence of prostate cancer in African Americans may be linked to deficiency of vitamin D (6, 8, 12). Therefore, vitamin D insufficiency has become a public health concern especially in the African-American population in the United States (8-9). Sunlight exposure may increase vitamin D synthesis in the skin and is thought to provide protection against prostate cancer. About 90-95% of the human vitamin D requirement comes from sunlight exposure to the skin (17). The elderly are at greatest risk of vitamin D deficiency because of their limited exposure to sunlight and less cutaneous synthesis of 7-dehydrocholesterol and, hence, lower production of vitamin D3 (23). There are many ecological and observational studies showing that sunlight exposure is inversely associated with prostate cancer risk (10, 17, 18). There are also epidemiological studies (19-21) suggesting that the high prostate cancer risk could be associated with ethnic groups with dark (tanned) skin since high skin melanin content may reduce the absorption of UV radiation (UVR). In most persons, cutaneous production of vitamin D3 from sunlight is the primary source of the vitamin and the remainder is obtained from dietary sources and supplements (15, 22). The synthesis of vitamin D depends on UVR and prostate cancer mortality increases significantly as the availability of UVR exposure decreases (11, 20). According to recent studies vitamin D level is predicted by season, African American ethnicity, age, income, body mass index, Gleason score and supplemental vitamin D intake (17, 24-28).
In the present investigation, we studied the relationship between vitamin D, UV exposure and prostate cancer risk in 91 cases and 92 controls. Research in the African-American population regarding the interactions between environmental factors and prostate cancer may help to explain the disparity in prostate cancer development.
Patients and Methods
Study population. We recruited ninety-one African-American men who were older than 40 years of age from the Washington DC area with histologically diagnosed adenocarcinoma of the prostate, prostate-specific antigen (PSA) of more than 3.5 ng/ml, and a positive digital rectal examination (DRE). We then identified and recruited 92 age and ethnicity matched (African-American) controls who were regularly screened, with PSA levels of less than 3.5 ng/ml, normal DRE and with no history of prostate cancer among first-degree relatives. PSA values were obtained at the time of diagnosis for cases and at the time of study enrollment for controls. Participants were recruited from the Division of Urology at the Howard University Hospital or from ongoing free prostate cancer screening program at the Howard University Cancer Center. The Howard University Institutional Review Board and Army Surgeon General's Human Subjects Research Review Board (HSRRB) approved the study protocol (IRB-02-MED-42) and written informed consent was obtained from all study participants. Detailed information about demographics and medical history was obtained through a structured in-person interview as described by Kanaan et al. (29).
Assessment of UVR exposure. Because cutaneous production of vitamin D greatly contributes to systemic vitamin D levels (14), we used occupational and physical activities as surrogate of sunlight exposure. Participants were stratified into groups: i) those who engaged in outdoor activities with walking or labor work, and ii) those who did not engage in any outdoor physical activity. Each participant answered questions from the validated UV questionnaire (30, 31). This questionnaire is designed to calculate the total amount of exposure to UV light from childhood until the time of interview. Participants were asked to assess such exposure during the following age categories; 0-5 years, 6-11 years, 12-17 years, 18-29 years, 30-39 years, and 40 years to age at diagnosis of prostate cancer, or age of data collection for the controls. These data were combined to give a total UVR exposure in hours per year. Each participant's cumulative sunlight exposure was assessed by a combination of his history of occupational and non-occupational sunlight exposure as described by Kanaan et al. (29).
Assessment of tanning potential. Normal human skin color can be classified either as constitutive pigmentation or facultative pigmentation (32). Constitutive pigmentation, the melanin content of unexposed areas of the skin, is a polygenic trait that is relatively unaffected by environmental factors. Facultative skin color is that which develops following exposure to a stimulant such as sunlight. Measurement of skin color was carried out using a computerized narrow-band reflectometer (Mexameter® MX 18, Courage+Khazaka electronic GmbH, Cologne, Germany) (33). Using two wavelengths, 568 nm (green light) and 660 nm (red light), the instrument records the reflectance of light emitted to the skin. The results are expressed in terms of melanin (M) index (0 to 100%). The inner arm is used to measure constitutive skin pigmentation. Measurements on the forehead and back of hand (facultative skin pigmentation) were taken for the exposed skin area. Three separate measurements of M were taken at all three sites and the average M value used in the analysis. The difference between constitutive (inner arm M) and facultative (average of forehead and back of hand, M) has been proposed as a quantitative index of sun exposure (tanning potential) that is related to cumulative lifetime sun exposure (34, 35).
General statistical description for the studied factors.
The number of participants, and the mean and SD for tanning potential (%) according to age group.
Serum 25-OH vitamin D assay. The measurement of the major circulating form of vitamin D, 25(OH)Vit D, is the gold standard for determining the vitamin D status (36). The quantitative determination of 25(OH)Vit D in serum was carried out by using an enzyme immunoassay from Immunodiagnostic Systems Ltd. (Immunodiagnostic Systems, Fountain Hills, AZ, USA). This assay is sensitive and can detect up to 5 ng/ml from a small (25 μl) sample size producing consistent results (37).
Statistical analysis. We employed several statistical methods to determine the association of prostate cancer with risk factors, age and environmental factors (38, 39). Prostate cancer status was described as a binary variable as the presence or absence of cancer. The environmental factors were reported as continuous variables. We analyzed three logistic models (40-42). The full model describes prostate cancer as the response, while age, tanning potential, sunlight and vitamin D are the predictors. The reduced model describes prostate cancer as the response, while age and tanning potential are predictors. The third logistic model describes prostate cancer as the response, while sunlight and vitamin D are predictors. Student's t-test was used to determine if there were differences in the four risk factors between cases and controls. Since the t-test showed age to be a significant factor, logistic regression analysis was carried out on the environmental factors by adjusting for age. Logistic models 1, 2 and 3 were used to analyze the associations of one, two and three factors with prostate cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for age. Estimates were considered statistically significant for two-tailed values of p<0.05. All analyses were carried out using Statistical Analysis Software (SAS Institute Inc., Cary, NC, USA).
Student's t-test comparing risk factors for prostate cancer in cases and controls.
Results
The participants had a mean age of 61.6 years (range=42-88), and mean vitamin D level of 28 (range=5.4-66) ng/ml, while sunlight exposure and tanning potential were 25,844 (range=3,508-18,5600) and 34 (range=0-100 respectively (Table I). Ninety-six percent of the cases and 83.7% of controls were older than 50 years (Table II).
The t-test revealed cases to be significantly older (p<0.001) and to have higher PSA levels (p<0.047) than controls, as shown in Table II. The lifetime cumulative sun exposure values and mean tanning potential did not differ between prostate cancer cases and controls (p<0.73 and p<0.21, respectively), nor did the mean serum vitamin D level (p<0.29) (Table III).
Logistic regression modeling showed that age and tanning potential were significantly associated with prostate cancer status (r2=0.133 and observed power=0.993 at the 0.05 level (model 1a; Table IV). Specifically, compared to the <50-year-old group, logistic regression showed a 6.6-fold and 7.08-fold increased likelihood of prostate cancer among men aged 60-70 (OR=6.61, p<0.003) or older than 70 years (OR=7.08, p<0.004) (Table IV). Sunlight and vitamin D were not significant at the 0.05 level (r2=0.133; observed power=0.974). On the other hand, tanning potential alone was a significant (p=0.05) risk factor for prostate cancer. Tanning potential was also significant (p=0.044) when adjusted for vitamin D and age (model 2a, Table V), whereas sunlight and vitamin D level were not (modeI 1b, Table IV). The results also showed that tanning potential alone was significantly associated with prostate cancer risk (p=0.05), while sunlight exposure and vitamin D level were not (model 1b, 1c; Table IV). Tanning potential was also significant (p=0.044) when adjusted for vitamin D level and age (model 2a; Table V). However, tanning potential was only marginally significant (p=0.064; model 2c) when adjusted for sunlight exposure and age, as well as for sunlight, vitamin D and age, respectively (p=0.058; model 3; Table VI).
Discussion
In the present study, we examined the association of serum vitamin D, skin tanning potential, and UV exposure with prostate cancer risk in African Americans. We found a significant association between skin tanning potential and prostate cancer at levels 0.05 and 0.044, as shown by model 1a and model 2b (Tables IV and V). However, our results showed no significant association between prostate cancer and UV exposure or serum vitamin D.
There are conflicting reports on the association between sunlight exposure, vitamin D and prostate cancer. Luscombe et al. (17) and Bodiwala et al. (19) found that decreased UVR exposure was associated with increased prostate cancer risk. According to John et al. (18) usual residence in a high solar radiation region or being born in the South was associated with reduced prostate cancer risk. Another study showed contradictory results that high levels of UVR exposure may be positively associated with the risk of prostate cancer mortality (7). Kanaan et al. (29) reported that early life sun exposure may reduce the risk of prostate cancer in African Americans. On the other hand, a multi-country study consisting of 33 countries worldwide failed to prove that sunlight exposure reduced the risk of prostate cancer (22). A population-based nested case–control study and meta-analysis only provided a limited support for the effect of sunlight on reducing prostate cancer (21). These different studies suggest that the association between sunlight exposure and prostate cancer risk is not well-established.
Standard logistic regression analysis for model 1.
Although our results did not show sunlight exposure to be associated with prostate cancer, tanning potential was. It is clear from our results that tanning potential was inversely related to prostate cancer. This can be explained by the fact that all our participants were dark-skinned and thus the UV absorption differences by melanin will be minimal. Therefore, the significant association between tanning potential and prostate cancer can be explained by the loss of skin pigment with age. This is supported by the significant role that greater age is associated with prostate cancer (Table II). Obviously the less skin pigment there is, the higher the potential for tanning. This means that African Americans with lighter skin color are at a reduced risk for developing prostate cancer. A study carried out by Colli and Grant reported that prostate cancer risk in black men did not decrease from sunlight exposure when compared to their Caucasian counterparts (43).
Standard logistic regression analysis results for model 2.
Standard logistic regression analysis results for model 3.
As in the case of sunlight exposure, we did not find significant association between serum vitamin D and prostate cancer. The mean 25(OH)Vit D concentrations in our African-American samples were higher than the 18.0 ng/ml reported by others (12, 24) but still lower than the cut-off value of 32.1 ng/ml (24) below which calcium absorption efficiency is reduced as a result of vitamin D deficiency. Most of our participants had 25(OH)Vit D values indicative of vitamin D deficiency; perhaps due to this we failed to show a significant association between circulating serum 25(OH)Vit D levels and prostate cancer. Recent studies also found no association of vitamin D uptake with prostate cancer risk (26-28). Cavalier et al. (25) recommend ensuring a patient's vitamin 25(OH)Vit D level is at 40 ng/ml in order to achieve 32 ng/ml. There are some studies supporting the idea that high levels of serum vitamin D have protection effects against prostate cancer (11, 20, 44, 45). A US study indicated that serum 1,25 vitamin D3 was negatively associated with prostate cancer restricted to men above a median age of 57 years (11). In addition, two more recent reports suggested that both circulating 25(OH)D3 and 1,25(OH)2D3 at median or higher levels confer a lower risk for prostate cancer progression (44, 45). There are also a number of studies demonstrating no inverse relationship between circulating vitamin D metabolite levels and risk of prostate cancer (46-48). Two recent studies concluded that there was no association of serum 25-OH vitamin D3 levels with subsequent prostate cancer risk (48, 49). Another study also reported that only the older group (>61 years) with plasma 25(OH)D3 lower than the median had a 57% reduction of cancer risk (50).
Ethnic/racial variations in 25(OH)Vit D concentrations have been reported in different populations. For example, a higher concentration was reported among non-Hispanic Caucasians and lower mean values of 25(OH)Vit D concentrations in Mexican Americans, non-Hispanic blacks (2) and African American men (26). These studies found no significant increased risk of prostate cancer for those with low vitamin D status (OR for <20 vs. ≥30 ng/ml =1.03, 95% CI=0.64-1.66). Our results which showed lack of association with vitamin D level (p<0.44) are consistent will this. Vitamin D deficiencies in people with darker color are common due to the high level of melanin in the skin. Melanin reduces the amount of UVR that reaches 7-dehydrocholesterol in the lower epidermis to produce pre-vitamin D (27-28). It is worth noting that recent reports have supported the hypothesis that pre-diagnostic serum 25(OH)Vit D is not important in prostate cancer incidence or progression (29-31).
A potential limitation of our study was selection bias: all our participants are residents in the Washington, DC metropolitan area, mostly receiving similar levels of sunlight. The Metropolitan area is located at a Latitude – 38° 53’ 42” N with Longitude – 77° 2’ 10” W and Altitude 11M conferring low UVR exposure. We measured 25(OH)Vit D using only a one-time serum sample and thus it may not reflect the long-term circulating vitamin D level. Multiple measurements with adequate follow-up would be required to obtain more reliable results. Therefore, further research needs to be directed for the identification of all biological, dietary, socioeconomic and genetic susceptibility factors. The research work should focus on the effect of sunlight on vitamin D synthesis at different times for a given period for large cohorts and collect comprehensive individual data from participants in DC, Maryland and Virginia. Findings from such work could show the amount of sun exposure required for production and maintenance of optimal serum vitamin D in African Americans.
In conclusion, the reduced logistic model, with prostate cancer as the response and age and tanning as the predictors may be a good model because the r2 value is the same as that for the full model. This study suggest an association between tanning potential and increased prostate cancer risk is indicative of the loss of skin pigment as a result of aging.
Acknowledgements
This work was supported by US Army Medical Research and Materiel Command (USAMRMC) [DAMD17-03-1-0069]
Footnotes
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Disclosure
We have no personal or financial conflicts of interest and have not entered into any agreement that could interfere with our access to the data on the research, or upon our ability to analyze the data independently, to prepare manuscripts, and to publish them.
- Received May 9, 2014.
- Revision received September 11, 2014.
- Accepted September 16, 2014.
- Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved