We observed strong support for the hypothesis that plasma selenium levels and SOD2 genotype interact to influence risk of presenting with aggressive prostate cancer at diagnosis in men with localized or locally advanced prostate cancer. Higher selenium levels alone were also slightly positively associated with worse prognostic risk at diagnosis, which largely reflected an association with higher Gleason sum. There was no association for SOD2 alone and prostate cancer aggressiveness in this population.
The median selenium level in this population (121.4 ng/mL) was comparable to that in several other studies, where the range of median (or mean) circulating selenium levels among healthy control or placebo groups was 108 to 141 ng/mL.1,5,7,8,14,23,25
The trend toward a slightly higher risk of aggressive disease for higher levels of selenium in this case population is unique and somewhat in contrast to several studies that reported decreased prostate cancer risk with higher selenium levels.1,2,4,5,7–10,14,17
However, some data indicate that the association between selenium and cancer risk may not be entirely linear and that higher doses could have null or adverse effects.
In SELECT, men receiving selenium supplementation had a median selenium level that was substantially higher (252 μg/L) than that of men in the current study (121 μg/L; range, 64 to 221 μg/L), and the trial reported null results for selenium supplementation versus placebo and incident (mainly early-stage) prostate cancer risk and a nonsignificant elevation in diabetes risk.25
In the large National Institutes of Health–American Association of Retired Persons Diet and Health Study, more than daily usage of multivitamins was associated with an elevated risk of incident advanced and fatal prostate cancer, in particular among men who also took individual supplements of selenium, β-carotene, or zinc or who had a family history of prostate cancer.35
Waters et al19
conducted a randomized controlled feeding study of selenium supplementation versus placebo in male dogs, the only other species besides humans to experience spontaneous prostate cancer. Dogs receiving selenium had significantly less DNA damage and more apoptosis in their peripheral-blood lymphocytes and prostate cells,19
and there was a U-shaped dose-response curve between toenail measures of selenium and extent of DNA damage in prostate tissue.36
In the Nutritional Prevention of Cancer Trial, selenium supplementation reduced total and prostate cancer incidence; however, this effect was limited to those with lower baseline circulating selenium levels (hazard ratio = 0.14; 95% CI, 0.03 to 0.61 for selenium levels < 106.4 ng/mL). Among men in the highest tertile (> 123.2 ng/mL), selenium supplementation was unassociated with prostate cancer risk, although in the positive direction (hazard ratio = 1.14; 95% CI, 0.51 to 2.59).13
Also, among those randomly assigned to selenium, being in the highest versus lowest tertile of circulating selenium at baseline was associated with an 88% increased risk of total cancer (P
Together, these data suggest that obtaining a certain level of selenium may confer some protection against prostate cancer; however, the relationship may not be linear, and caution is warranted before assuming that obtaining increasingly higher levels confers increased benefit.
The effect of selenium status on prostate cancer may also depend on how it interacts with components of the oxidative stress pathway, as evidenced by the current study. The observed 40% decreased risk of aggressive prostate cancer associated with higher selenium among men with the AA variant (P for trend = .06) was consistent and expands on our previous findings in the PHS. However, an important difference was that in the current study, men with a V allele had an elevated risk of aggressive disease with higher selenium levels, and there was no such trend in the PHS. Differences in study design and patient population may explain this apparent inconsistency. In particular, PHS focused on prediagnostic selenium levels from years before diagnosis, in contrast to the present study, which examined levels at or shortly after diagnosis. Also, we contrasted cases only, whereas the PHS compared men with and without prostate cancer diagnoses to examine risk of developing total or advanced prostate cancer. Furthermore, in the PHS, the significant inverse relation was observed only for risk of developing advanced-stage, not localized, prostate cancer; and in the current study, we examined only patients that had stage T3 disease or less. Despite these differences, the findings converge on demonstrating an interaction of selenium with SOD2 genotype in prostate cancer.
Several other studies have reported on possible effect modification by SOD2
on the relationship between dietary factors and prostate cancer incidence.37–40
In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, having SOD2
AA genotype was associated with an increased risk of developing prostate cancer, in particular among those with lower vitamin E intake who were also smokers, although there was no effect modification by selenium level.38
In the Carotene and Retinol Efficacy Trial, SOD2
alone was not associated with prostate cancer risk, but among VV carriers, never versus ever use of vitamin supplements or greater iron intake was associated with double the risk of incident prostate cancer.37,40
In contrast, SOD2
AA genotype (v
VV or VA) was associated with more than 2.5-fold elevation in risk of high-grade prostate tumors in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, whereas there was no evidence for an interaction by vitamin E or β-carotene.39
A few other studies have also reported a higher frequency of A alleles among prostate cancer patients versus controls or healthy adults.41,42
Further evidence that SOD2
genotype modifies diet or lifestyle associations with carcinogenesis comes from studies of breast,43–48
The observed interaction between SOD2
and selenium levels may reflect the dual roles of selenium as a pro- and antioxidant, depending on dose, form, and function of other enzymes.51,52
The AA variant of SOD2
may be more effective at transporting the enzyme through the mitochondrial membrane, thereby increasing breakdown of superoxide radicals into hydrogen peroxide.30
If there is sufficient selenium, then (selenium-dependent) GPX can next act to efficiently break down hydrogen peroxide into water. However, if there is not sufficient selenium, the GPX reaction is halted, and a buildup of hydrogen peroxide may occur, leading to toxicity, oxidation, propensity for DNA damage, and increased cancer risk. This may be one way in which lower versus higher selenium levels and the AA variant could be associated with an increased risk of aggressive prostate cancer.26
The direct relation of higher selenium with more aggressive disease among carriers of the V allele was unexpected and has not previously been reported. One explanation might be that in men with established cancer, antioxidants may promote cancer cell survival through an antiapoptotic mechanism by neutralizing the higher levels of reactive oxygen species found in cancer cells. Alternatively, given the cross-sectional nature of our study, it could be that prostate tumors that develop despite high selenium status tend to have higher Gleason grade. However, the interaction and different associations observed based on SOD2
argues against this reverse causality explanation. One could speculate that if there is chronic lower normal SOD2
activity and high superoxide anion production as a result of high concentrations of selenite, then there may be an imbalance toward oxidative stress that cannot be fully compensated by GPX or catalase actions alone.51
Finally, this finding may be a result of chance and warrants further confirmation in humans.
This study has several limitations that must be considered. It was cross-sectional, and we cannot entirely rule out the possibility that the slight positive association for selenium and risk of aggressive disease was a result of patients with worse clinical features taking selenium supplements out of concern about their diagnosis. However, most blood was donated shortly after diagnosis, and the strong interaction with SOD2 genotype argues against this. Other limitations include our inability to adjust for potential confounding factors, such as body size or diet, and lack of racial diversity.
In conclusion, this cross-sectional analysis of 489 men with prostate cancer provides evidence that selenium levels interact with SOD2 genotype to influence the risk of presenting with aggressive prostate cancer at diagnosis. Among the approximate 25% of men with the AA genotype, having greater selenium levels may protect against aggressive disease. However, for the 75% men who carry a V allele, higher selenium levels might increase the likelihood of having worse tumor characteristics. Together, these data underscore the importance of genotype for understanding the potential benefits and dangers of selenium on prostate cancer and may, in part, explain apparently conflicting results from previous studies. Complete interpretation of results from SELECT may depend on assessment of SOD2 genotype in trial participants.