GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)
Lower 25-hydroxyvitamin D2/D3 levels at melanoma diagnosis are associated with thicker primaries and poorer survival. We postulated that this might relate to the deleterious effect of systemic inflammation as 25-hydroxyvitamin D2/D3 levels are inversely associated with levels of C-reactive protein. 2182 participants in the Leeds Melanoma Cohort (median follow up 7.98 years) provided data on drug exposure, co-morbidities and a serum 25-hydroxyvitamin D2/D3 level at recruitment. Factors reported to modify systemic inflammation (low vitamin D levels, high body mass index (BMI), use of aspirin or non-steroidal anti-inflammatory drugs or smoking were tested as predictors of microscopic ulceration (in which primary tumours are inflamed) and melanoma specific survival (MSS). Ulceration was independently associated with lower 25-hydroxyvitamin D2/D3 levels (OR=0.94 per 10nmol/L, 95% CI 0.88–1.00, p=0.05) and smoking at diagnosis (OR=1.47, 95% CI 1.00–2.15, p= 0.04). In analyses adjusted for age and sex, a protective effect was seen of 25-hydroxyvitamin D2/D3 levels at diagnosis on melanoma death (OR=0.89 per 10nmol/L, 95% CI 0.83–0.95, p<0.001) and smoking increased the risk of death (OR=1.13 per 10 years, 95% CI 1.05–1.22, p=0.001). In multivariable analyses (adjusted for tumour thickness) the associations with death from melanoma were low 25-hydroxyvitamin D2/D3 level at recruitment (<20 nmol/L vs. 20–60 nmol/L, HR=1.52, 95% CI 0.97–2.40, p=0.07) and smoking duration at diagnosis (HR=1.11, 95% CI 1.03–1.20, p=0.009). The study shows evidence that lower vitamin D levels and smoking are associated with ulceration of primary melanomas and poorer MSS. Further analyses are necessary to understand any biological mechanisms that underlie these findings.
Genetic and epigenetic analyses of the human 9p21 locus indicate that modifications of ARF occur independently of p16 inactivation in human melanoma and suggest that ARF is more frequently inactivated than p16.
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