In a study population where little PSA screening occurred, we found a previously not reported relation between serum selenium levels, smoking and prostate cancer risk: Smokers with serum selenium levels in the two lower tertiles (≤80 μg/L) experienced a higher cumulative incidence of prostate cancer than smokers in the high serum selenium tertile. In hypothesis generating explorative analyses, we found indications that the association between serum selenium levels and prostate cancer risk was modified by genetic polymorphisms, in the OGG1 gene (rs125701) and MnSOD gene (rs2758331- linked to rs4880).
The ULSAM cohort is population based and homogenous as regards the ethnic background and the age of the participants [42
]. The participant rate was high and the follow-up up to 34 years almost complete through using linkage to national registers with high coverage. ULSAM has a thorough characterization of factors influencing serum selenium levels including information on smoking habits[42
]. Only few prostate cancers were detected by PSA-screening and our results thus mainly pertain to clinically relevant prostate cancer with a high risk of progress.
For cancer studies, ULSAM is comparatively small and modest or weak associations may go undetected: our data indicate an overall modest inverse relation of serum selenium level with prostate cancer risk, which we could not substantiate. The serum selenium levels and co- variates were measured at a median of 23 years before diagnosis, a disadvantage, which however is shared with the other studies in the field [10
]. In a Swedish population the range of selenium exposure is limited, with few high serum selenium level values. The size of the study implies that our analyses of the interaction of gene polymorphism and serum selenium levels are of an exploratory character. Another disadvantage is that a proxy SNP was used for the analysis of the main MnSOD
polymorphism which made a detailed analysis on a molecular level unattainable.
Our finding of an increased risk for prostate cancer in smokers with low serum selenium is a new finding. As smoking increases oxidative damage, it is not biologically unreasonable. This relation may in other studies have been masked by the strong competing risk of concomitant early death from other causes, mainly cardiovascular disease, predominantly in smokers. If smoking is associated with both early death and risk of prostate cancer later in life, conventional time to event analyses may give a false impression that smoking protects from prostate cancer since methods traditionally employed assumes that censoring is non-informative. We noted and analysed a similar pattern for obesity in the ULSAM cohort [59
]. This type of competing risk problem may be particularly evident in this study representing a pre-screening era where the median age at diagnosis of prostate cancer was 73 years of age. Thus, a screening program for prostate cancer introducing long lead times may alter this pattern.
Our hypothesis generating results that serum selenium levels and the polymorphic genes OGG1
involved in the protection from oxidative stress, act concurrently in the defence of prostate cancer development are in accord with previous knowledge [2
]. A recent nested case-control study within the Physicians Health Study [24
] analyzing polymorphisms within the selenoprotein gene, SEP15 found genetic variants associated with prostate cancer mortality and also modifying the association of serum selenium with prostate cancer survival. If, as the recent report suggest [24
] and our study may be interpreted, only subgroups of men would benefit from high serum selenium levels, then beneficial effects of supplementation in interventional studies may pertain only to subgroups and therefore be difficult to detect. There was an overall lack of effect of selenium supplementation in the SELECT trial [20
]. The trial inclusion criteria did neither enrich a study population with low baseline selenium levels nor patients defined by pre-specified genetic polymorphisms. The differences in results from the interventional study, ours and another recent observational study [24
] are not contradictory but rather emphasize the possibility for interventional studies in predefined groups of men with low selenium concentrations and certain genetic profiles. Due to the limited size of our study, the impact of genetic variation in relation to smoking being a risk factor for prostate cancer was not possible to analyse further.