Susan Leake

Serum 25-Hydroxyvitamin D3 Levels Are Associated With Breslow Thickness at Presentation and Survival From Melanoma

PURPOSE A cohort study was carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma. METHODS A pilot retrospective study of 271 patients with melanoma suggested that vitamin D may protect against recurrence of melanoma. We tested these findings in a survival analysis in a cohort of 872 patients recruited to the Leeds Melanoma Cohort (median follow-up, 4.7 years). RESULTS In the retrospective study, self-reports of taking vitamin D supplements were nonsignificantly correlated with a reduced risk of melanoma relapse (odds ratio = 0.6; 95% CI, 0.4 to 1.1; P = .09). Nonrelapsers had higher mean 25-hydroxyvitamin D(3) levels than relapsers (49 v 46 nmol/L; P = .3; not statistically significant). In the cohort (prospective) study, higher 25-hydroxyvitamin D(3) levels were associated with lower Breslow thickness at diagnosis (P = .002) and were independently protective of relapse and death: the hazard ratio for relapse-free survival (RFS) was 0.79 (95% CI, 0.64 to 0.96; P = .01) for a 20 nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum 25-hydroxyvitamin D(3) levels on RFS. CONCLUSION Results from the retrospective study were consistent with a role for vitamin D in melanoma outcome. The cohort study tests this hypothesis, providing evidence that higher 25-hydroxyvitamin D(3) levels, at diagnosis, are associated with both thinner tumors and better survival from melanoma, independent of Breslow thickness. Patients with melanoma, and those at high risk of melanoma, should seek to ensure vitamin D sufficiency. Additional studies are needed to establish optimal serum levels for patients with melanoma.

Vitamin D receptor gene polymorphisms, serum 25-hydroxyvitamin D levels, and melanoma: UK case-control comparisons and a meta-analysis of published VDR data

We have carried out melanoma case-control comparisons for six vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) and serum 25-hydroxyvitamin D(3) levels in order to investigate the role of vitamin D in melanoma susceptibility. There was no significant evidence of an association between any VDR SNP and risk in 1028 population-ascertained cases and 402 controls from Leeds, UK. In a second Leeds case-control study (299 cases and 560 controls) the FokI T allele was associated with increased melanoma risk (odds ratio (OR) 1.42, 95% confidence interval (CI) 1.06-1.91, p=0.02). In a meta-analysis in conjunction with published data from other smaller data sets (total 3769 cases and 3636 controls), the FokI T allele was associated with increased melanoma risk (OR 1.19, 95% CI 1.05-1.35), and the BsmI A allele was associated with a reduced risk (OR 0.81, 95% CI 0.72-0.92), in each instance under a parsimonious dominant model. In the first Leeds case-control comparison cases were more likely to have a higher body mass index (BMI) than controls (p=0.007 for linear trend). There was no evidence of a case-control difference in serum 25-hydroxyvitamin D(3) levels. In 1043 incident cases from the first Leeds case-control study, a single estimation of serum 25-hydroxyvitamin D(3) level taken at recruitment was inversely correlated with Breslow thickness (p=0.03 for linear trend). These data provide evidence to support the view that vitamin D and VDR may have a small but potentially important role in melanoma susceptibility, and putatively a greater role in disease progression.

Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate

AIM A melanoma case-control study was conducted to elucidate the complex relationship between sun exposure and risk. METHODS Nine hundred and sixty population-ascertained cases, 513 population and 174 sibling controls recruited in England provided detailed sun exposure and phenotype data; a subset provided serum 25-hydroxyvitamin D(2)+D(3) levels. RESULTS Phenotypes associated with a tendency to sunburn and reported sunburn at ≥ 20 years of age were associated with increased melanoma risk (odds ratio (OR) 1.56, 95% confidence intervals (CI) 1.23-1.99). Holiday sun exposure was not associated with an increased melanoma risk although this may be in part because reported sun exposure overall was much lower in those with a sun-sensitive phenotype, particularly among controls. Head and neck melanoma was associated with less sun exposure on holidays at low latitudes (OR 0.39, 95% CI (0.23-0.68) for >13 h/year compared to <3.1). Overall the clearest relationship between reported sun exposure and risk was for average weekend sun exposure in warmer months, which was protective (OR 0.67, 95% CI 0.50-0.89 for highest versus lowest tertile of exposure). Serum vitamin D levels were strongly associated with increased weekend and holiday sun exposure. CONCLUSIONS Sun-sensitive phenotypes and reported sunburn were associated with an increased risk of melanoma. Although no evidence was seen of a causal relationship between holiday sun exposure and increased risk, this is consistent with the view that intense sun exposure is causal for melanoma in those prone to sunburn. A protective effect of regular weekend sun exposure was seen, particularly for limb tumours, which could be mediated by photoadaptation or higher vitamin D levels.

Melanocytic nevi, nevus genes and melanoma risk in a large case-control study in the United Kingdom

Background: Increased number of melanocytic nevi is a potent melanoma risk factor. We have carried out a large population-based case-control study to explore the environmental and genetic determinants of nevi and the relationship with melanoma risk. Methods: We report nevus phenotype in relation to differing patterns of sun exposure, inherited variation at loci shown in recent genome-wide association studies to be nevus genes, and risk. Results: Increased numbers of nevi were associated with holiday sun exposure, particularly on intermittently sun-exposed body sites (test for Ptrend < 0.0001). Large nevi were also associated with holiday sun exposure (P = 0.002). Single nucleotide polymorphisms (SNP) on chromosomes 9 and 22 were associated with increased numbers of nevi (P = 0.04 and P = 0.002 respectively) and larger nevi (P = 0.03 and P = 0.002), whereas that on chromosome 6 was associated only with large nevi (P = 0.01). Melanoma risk was associated with increased nevus count, large nevi, and atypical nevi for tumors in all body sites (including rare sites) irrespective of age. The risk persisted when adjusted for inheritance of nevus SNPs. Conclusions: The at-risk nevus phenotype is associated with behaviors known to increase melanoma risk (holiday sun exposure). Although SNPs on chromosomes 6, 9, and 22 were shown to be nevus genes, they explained only a small proportion of melanoma risk and nevus phenotype; therefore, several nevus genes likely remain to be identified. Impact: This article confirms the importance of nevi in melanoma pathogenesis and increases understanding of their genetic determinants. Cancer Epidemiol Biomarkers Prev; 19(8); 2043–54. ©2010 AACR.

The determinants of periorbital skin ageing in participants of a melanoma case-control study in the U.K

Background  Skin ageing is said to be caused by multiple factors. The relationship with sun exposure is of particular interest because the detrimental cutaneous effects of the sun may be a strong motivator to sun protection. We report a study of skin ageing in participants of an epidemiological study of melanoma.

Relationship between sunbed use and melanoma risk in a large case‐control study in the United Kingdom

Dear Editor, A systematic review of 19 studies reported a 15% increased risk of melanoma (95% confidence interval (CI) 1.00–1.31) associated with ever use of sunbeds. A recent Australian study by Cust et al. demonstrated an increased risk of earlyonset melanoma (<40 years) associated with ever use of sunbeds (adjusted odds ratio (OR) 1.41, 95% CI 1.01–1.96). Concurrently with the Australian study and using the same questionnaire, we investigated the relationship between sunbed use and melanoma at any age in the United Kingdom. A similar estimate in the UK, which has higher sunbed usage, would imply that sunbed usage is a major etiological factor for melanoma. Nine hundred and fifty-nine population-ascertained incident melanoma cases diagnosed from September 2000 to December 2005 (age 17–76 years at diagnosis, 22% <40 years at diagnosis), 513 population-ascertained controls and 174 sibling controls were recruited to a case–control study whereby comprehensive sun exposure data, including a life-long residence calendar, were collected as described previously. Participants were asked about sunbed or sunlamp use (ever versus never) and about locations they were used. Data were collected on age at first and last use and number of lifetime sessions. Years since first use was calculated and these variables were categorized as presented by Cust et al.: never, <25, 25 years; none, 1–10, >10 sessions; never, 4, >4 and 14, >14 years, respectively. A proxy for sun sensitivity phenotype (categorized as sun-sensitive or not sun-sensitive) was derived, as described previously. As far as possible, we repeated the analyses as reported by Cust et al. Spearman correlations, Wilcoxon rank-sum tests and Pearson chi-squared tests were performed for pair-wise associations. ORs and 95% CIs were calculated from unconditional logistic regression models using data from cases and population-ascertained controls to assess the sunbed variables as predictors of melanoma. Population controls were significantly older than cases (median age diagnosis/interview 58 and 53 years, respectively, p < 0.0001) and more educated (v(3) 1⁄4 6.9, p 1⁄4 0.03). Cases were significantly more likely to have family history of melanoma in first or second degree relatives compared with controls (v(1) 1⁄4 8.0, p 1⁄4 0.01). The primary analyses comparing cases and population controls were therefore adjusted for age (examined as a trend over quartiles), sex, highest educational level (primary/secondary school, sixth form/vocational training, university/post graduate examined as a trend), sun sensitivity phenotype, selfreported family history in 1st or 2nd degree relatives (none, any) and cumulative lifetime total sun exposure (examined as a trend over quartiles). These analyses were repeated in the subset of 157 cases with matched siblings using conditional logistic regression models, adjusted for all of the above-listed factors except family history. We also performed some subgroup analyses stratifying by the factors defined by Cust et al. (sex, age at diagnosis/interview, sun sensitivity phenotype, nevi, lifetime total sun exposure) and also average number of sunburns during lifetime. In our case–control study, we found the sun exposure measure most associated with risk was a protective effect of regular weekend sun exposure. We therefore repeated the analyses adjusting for this measure but there was no effect on the results (data not shown). The locations where sunbeds were used were private home (54%), tanning salons (34%), gyms/spas (32%), hairdressers/beauty salons (13%) and hospital/medical facilities (9%). In analyses considering cases and population controls, younger age was associated with number of sessions (rho 1⁄4 0.37, p < 0.0001) and ever versus never use (means 49 and 60 years, respectively, p < 0.0001). Females reported a higher number of sessions compared with males (p < 0.0001) and 57% of females reported ever use compared with 38% of males (v(1) 1⁄4 52.0, p < 0.0001). Sun sensitivity phenotype and educational level were not associated with sunbed use. In multiple regression analyses, ever-use of sunbeds was not a significant risk factor for melanoma (adjusted OR 1.06, 95% CI 0.83–1.36, Table 1). Age at first use of sunbeds showed a small non-significant increased risk for use <25 years compared with never use (OR 1.16, 95%CI 0.84–1.62), as did age at last use <25 years (OR 1.49, 95% CI 0.95–2.34). Number of sessions and years since first use did not show an increasing trend effect on melanoma risk. The secondary analyses comparing cases with sibling controls gave an OR of 1.10 (95% CI 0.63–1.94) for ever versus never use (Table 1). Having >10 sessions conferred an OR of 1.27 compared with never use (95% CI 0.63–2.55, ptrend 0.54). If we further examine the number of sessions categorized according to our controls distribution (none, 1–20, >20), having >20 sessions conferred an OR of 1.49 compared with never use (95% CI 0.70–3.17, ptrend 0.35). Age at Le tt er to th e E di to r

Assessing the incremental contribution of common genomic variants to melanoma risk prediction in two population-based studies

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.