May Chan

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL

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 familys mutations) and the Netherlands (c.225_243del19, 90% of familys 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.

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

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.

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.

Predictors of Sun Protection Behaviors and Severe Sunburn in an International Online Study

Background: The incidence of melanoma continues to increase in many countries, and primary prevention of melanoma includes avoidance of sunburn as well as adequate sun protection behavior. The aim of this study was to examine the prevalence of self-reported sun protection behaviors and sunburn in users of the Internet, and to identify the demographic, clinical, and attitudinal/motivational correlates of sun protection behaviors. Methods: Self-report data were gathered on behalf of the GenoMEL consortium using an online survey available in 10 different languages, and 8,178 individuals successfully completed at least 80% of survey items, with 73% of respondents from Europe, 12% from Australia, 7% from the United States, 2% from Israel, and 6% from other countries. Results: Half of all respondents and 27% of those with a previous melanoma reported at least one severe sunburn during the previous 12 months. The strongest factors associated with sun protection behavior were perceived barriers to protection (β = −0.44/β = −0.37), and respondents who reported a positive attitude toward suntans were less likely to protect (β = −0.16/β = −0.14). Reported use of protective clothing and shade, as well as avoidance of midday sun exposure, were more strongly related to reduced risk of sunburn than sunscreen use. Conclusions: Despite widespread dissemination of public health messages about the importance of sun protection, a substantial proportion of this international sample, including respondents with a previous melanoma, reported inadequate sun protection behaviors resulting in severe sunburn. Impact: Future strategies to decrease sunburn should target the practical, social, and psychological barriers associated with nonuptake of sun protection. Cancer Epidemiol Biomarkers Prev; 19(9); 2199–210. ©2010 AACR.

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.

Melanoma sentinel node biopsy and prediction models for relapse and overall survival

Background:To optimise predictive models for sentinal node biopsy (SNB) positivity, relapse and survival, using clinico-pathological characteristics and osteopontin gene expression in primary melanomas.Methods:A comparison of the clinico-pathological characteristics of SNB positive and negative cases was carried out in 561 melanoma patients. In 199 patients, gene expression in formalin-fixed primary tumours was studied using Illuminas DASL assay. A cross validation approach was used to test prognostic predictive models and receiver operating characteristic curves were produced.Results:Independent predictors of SNB positivity were Breslow thickness, mitotic count and tumour site. Osteopontin expression best predicted SNB positivity (P=2.4 × 10−7), remaining significant in multivariable analysis. Osteopontin expression, combined with thickness, mitotic count and site, gave the best area under the curve (AUC) to predict SNB positivity (72.6%). Independent predictors of relapse-free survival were SNB status, thickness, site, ulceration and vessel invasion, whereas only SNB status and thickness predicted overall survival. Using clinico-pathological features (thickness, mitotic count, ulceration, vessel invasion, site, age and sex) gave a better AUC to predict relapse (71.0%) and survival (70.0%) than SNB status alone (57.0, 55.0%). In patients with gene expression data, the SNB status combined with the clinico-pathological features produced the best prediction of relapse (72.7%) and survival (69.0%), which was not increased further with osteopontin expression (72.7, 68.0%).Conclusion:Use of these models should be tested in other data sets in order to improve predictive and prognostic data for patients.

Clinical and genetic findings in an Ashkenazi Jewish population with colorectal neoplasms

The authors evaluated the frequency of the carrier status of three ancestral colorectal neoplasm‐associated mutations (APC:I1307K, BLMAsh, and MSH2*1906G>C) found in the Jewish population among a case series with documented colorectal neoplasms. They further compared family and personal histories plus environmental exposures of the carriers and noncarriers of the I1307K mutation and examined clinical differences with regard to the colorectal neoplasms and the specific molecular genetic changes in these lesions.

Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK

Background CDKN2A mutations confer a substantial risk of cutaneous melanoma; however, the magnitude of risk is uncertain. Methods The study estimated the hazard ratio (HR) and the average age specific cumulative risk (ie, penetrance) of reported melanoma for CDKN2A mutation carriers in case families using a modified segregation analysis of the first and higher degree relatives of 35 population-based cases. The study sample included 223 relatives of 13 melanoma cases diagnosed when aged 18–39 years from Melbourne, Sydney and Brisbane, Australia, and 322 relatives of 22 melanoma cases diagnosed at any age from Yorkshire, UK. Results The estimated HR for melanoma for mutation carriers relative to the general population decreased with regions of increasing ambient ultraviolet (UV) irradiance, being higher for the UK than Australia (87, 95% CI 50 to 153 vs 31, 95% CI 20 to 50, p=0.008), and across Australia, 49 (95% CI 24 to 98) for Melbourne, 44 (95% CI 22 to 88) for Sydney, and 9 (95% CI 2 to 33) for Brisbane (p=0.02). Penetrance did not differ by geographic region. It is estimated that 16% (95% CI 10% to 27%) of UK and 20% (95% CI 13% to 30%) of Australian CDKN2A mutation carriers would be diagnosed with melanoma by age 50 years, and 45% (95% CI 29% to 65%) and 52% (95% CI 37% to 69%), respectively, by age 80 years. Conclusions Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live.

25-Hydroxyvitamin D2 /D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort.

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. 2,182 participants in the Leeds Melanoma Cohort (median follow‐up 7.98 years) provided data on drug exposure, comorbidities and a serum 25‐hydroxyvitamin D2/D3 level at recruitment. Factors reported to modify systemic inflammation (low vitamin D levels, high body mass index, use of aspirin or nonsteroidal anti‐inflammatory drugs or smoking were tested as predictors of microscopic ulceration (in which primary tumors are inflamed) and melanoma‐specific survival (MSS). Ulceration was independently associated with lower 25‐hydroxyvitamin D2/D3 levels (odds ratio (OR) = 0.94 per 10 nmol/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 10 nmol/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 tumor thickness) the associations with death from melanoma were low 25‐hydroxyvitamin D2/D3 level at recruitment (<20 nmol/L vs. 20–60 nmol/L, hazard ratio (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.