The lack of a simple cumulative relationship between melanoma risk and sun exposure has caused difficulties in interpreting and conveying the nature of risk to the public. This has further recently been compounded by concerns that low levels of vitamin D, which might result from sun avoidance designed to reduce melanoma risk, could have negative effects on health generally (17
We therefore carried out a case-control study addressed to better understanding the relationship between sun exposure and risk in a population living at high latitude. The study benefits from a large sample size, and a very detailed validated sun exposure questionnaire, developed and used internationally. We have tested for multiple putative risk factors, so that p-values presented must be interpreted bearing this in mind. The limitations also include those of case-control studies generally, namely the possibility of recruitment and recall of information biases. Comparison with cancer registry data for the geographical area showed that the sample of cases was reasonably representative of the total melanoma population except that the study did not recruit over the age of 75 years, and as there were fewer elderly patients we therefore recruited fewer participants with head and neck tumours. Population controls were less deprived than the cases, which is likely to represent participation bias in controls. We recruited sibling controls as a useful additional comparison group, less subject to bias of ascertainment, although this method of control selection does produce less power due to shared genes and shared exposures. The number of siblings recruited was disappointing and we therefore used the sample as a secondary comparison group, but the results of this study do show the value of using two control groups in that we were able to demonstrate effects of similar magnitude in both groups. In order to further investigate the protective effect of regular weekend sun exposure we sought evidence for a possible role for vitamin D and a limitation of the study is that we had incomplete data collection on use of vitamin D supplements and serum vitamin D measurements from only a sample of the controls. Furthermore we had only one measure of vitamin D, although a recent paper has suggested that in screening cohorts at least that vitamin D levels are relatively stable over time (19
). The sample was also taken after diagnosis in cases and the level might therefore have been modified by behaviours after diagnosis.
Phenotypic characteristics associated with increased risk of melanoma were as reported in many case-control studies, and the ORs reported here were very similar to those reported in Gandini’s meta-analysis (3
). The association of sun-sensitive phenotypes with an increased melanoma risk is entirely consistent with recent findings in genome-wide association studies, in which the most significant genetic associations with melanoma were in genes determining pigmentation phenotypes (20
). We report data to support the view, however, that the relationship between phenotypes and melanoma risk is complicated, since sun-sensitive individuals reported less sun exposure than those with more sunburn resistant skin.
The study showed a clear relationship between reported sunburn and overall melanoma risk. The pattern of sun exposure most predictive of sunburn was holiday sun exposure, so that these data are supportive of previously reported studies including our pooled data analysis (4
) that intermittent sun exposure sufficient to cause burning is the major risk factor for melanoma overall. This case-control study showed no evidence, however, for a relationship between reported intermittent or recreational sun exposure and increased melanoma risk. Indeed there was even a suggestion of a protective effect. A previous large UK case-control study also showed little evidence of an effect of sunny holidays on risk (23
). Fair skinned controls reported less sun exposure than darker skinned controls, which is consistent with recently reported data from a healthy twin study (24
) in which vitamin D levels were reported to be lower in those with sun-sensitive phenotypes. It is possible that the relationship between risk and sunny holidays was weaker in both these studies because of recall bias. Sun-sensitive people were shown in this study moreover to be both at increased risk and to report less sun exposure than darker skinned individuals and this complexity may make the results of the usual case-control comparisons unclear. It is also possible that as the controls in our study were of slightly higher socioeconomic status than cases they had more access to sunny holiday sun exposure, although we have attempted to adjust for this using a measure of social deprivation.
Risk of melanoma on the head and neck () showed some association with higher weekday sun exposure in cooler months, although the pattern was irregular, and with lower sunny holiday exposure, consistent with previous published data to suggest that melanoma in these sites is associated with occupational or chronic sun exposure in individuals postulated to have less access to sunny holidays. We hypothesize that we were able to estimate the risk of melanoma associated with this type of sun exposure in temperate climates better in this case-control study than in our previous pooled data analysis because we had much more detailed data on different patterns of sun exposure, which was the main purpose and strength of this study.
The study shows a statistically significant protective effect of higher weekend sun exposure after adjustment for a measure of deprivation, and this behavior was associated with higher vitamin D levels. These data support the hypothesis that, whilst sunburn is a risk factor for melanoma, regular sun exposure may also be protective for those living at high latitude. There was some weak evidence for this in our previous pooled data analysis, in that at higher latitudes there was a non-significant protective effect of higher total sun exposure (4
). In the study reported here much more detailed sun exposure data were collected, and it is therefore possible in the case-control study to look at weekend sun exposure, which was not possible in the previous pooled data analysis. Although there was no statistically significant differences for sibling controls and cases the case-sibling control comparisons showed similar risk estimates and provide supportive evidence for this complex relationship between sun exposure and melanoma risk.
A protective effect of regular weekend sun exposure on melanoma risk might be mediated by photoadaption or as a result of higher consequent vitamin D levels, or the observation in this study may reflect bias due to the recruitment of controls of higher socioeconomic status. We utilized data on serum vitamin D levels to investigate this further. We have shown that greater reported weekend sun exposure was associated with higher vitamin D levels, supporting the hypothesis that a protective effect of weekend sun exposure might be mediated via higher levels of vitamin D. We have previously reported a case-control comparison for serum vitamin D levels (9
) in a smaller sample set, in which we saw no significant differences between cases and controls. The adjusted OR per 20 nmol/L increase of serum vitamin D across seasons was 0.94 (95% CI 0.79-1.12) (9
). In the current analysis the serum vitamin D levels were not quite independently protective for melanoma (OR=0.89, 95% CI 0.76-1.04 per 20 nmol/L increase) in a comparison between cases and population controls, but cases had significantly lower vitamin D levels than their sibling controls in the small subset available for this analysis. These data therefore support the hypothesis that a protective effect of weekend sun exposure might be mediated via higher levels of vitamin D synthesis. Since vitamin D levels were measured some months post-diagnosis, it is possible however that this difference may reflect subsequent sun avoidance in cases, although equally cancer patients often start to supplement their diet after diagnosis.
There are few published data to suggest a protective role for vitamin D in melanoma susceptibility: a recent cohort study for example reported no protective effect of supplemental vitamin D intake on melanoma risk although serum levels were not measured (8
), and from the paper it would appear that the authors were not able to adjust for sun exposure. We considered whether photoadaption was a more likely explanation of the protective effective of weekend sun exposure. That there was some protective effect of weekend sun exposure for truncal melanoma as well as melanoma on the limbs, (where photoadaption is likely to be less marked), argues against the hypothesis that photoadaption may be the means by which weekend sun exposure might protect. Furthermore in our study we saw a protective effect for melanoma even in non-sun exposed rare sites such as acral lentiginous and genital melanoma. Which might suggest that photoadaption is a less likely explanation. Data moreover suggest that photoadaption does not protect against the sunburn-induced immunosuppression (25
) which is thought central to melanoma carcinogenesis. Clearly further studies are needed to understand the means by which moderate sun exposure may be protective for melanoma.
In conclusion, this large study has confirmed that sunburn and sun-susceptible phenotypes are associated with melanoma risk. It has provided important information to support the view that, although sunburn is associated with melanoma, regular weekend sun exposure may be protective for melanoma in populations living at high latitude. The data suggest that this effect may be mediated at least in part by higher vitamin D levels, but photoadaption is an alternative hypothesis.
Data presented here suggest that individuals with sun-sensitive skin types are at increased risk of melanoma, and advice to them should be to avoid sunburn and behaviours associated with sunburn such as sunbathing. The possibility that low vitamin D levels may be a risk factor for melanoma and are certainly harmful to health generally, means that such fair skinned people should consider taking vitamin D supplements (at doses recommended by their local health authorities), if they are sun avoidant. For non-sun-sensitive individuals the data suggest that regular moderate sun exposure may be protective for melanoma and is shown to be associated with higher vitamin D levels. In these individuals therefore, not least because of the beneficial effects of vitamin D to health generally, there is an argument to suggest that regular sun exposure should be supported in countries with relatively low levels of ambient UV radiation, provided that no burning occurs. Sunburn and large cumulative sun exposures should be avoided. Comparison of these data with those from sunnier countries is required.