Biologic markers of sun exposure and melanoma risk in women: pooled case-control analysis.

A model has been proposed whereby melanomas arise through two distinct pathways dependent on the relative influence of host susceptibility and sun exposure. Such pathways may explain site-specific patterns of melanoma occurrence. To explore this model, we investigated the relationship between melanoma risk and general markers of acute (recalled sunburns) and chronic (prevalent solar keratoses) sun exposure, stratified by anatomic site and host phenotype. Our working hypothesis was that head and neck melanomas have stronger associations with solar keratoses and weaker associations with sunburn than trunk melanomas. We conducted a collaborative analysis using original data from women subjects of 11 case-control studies of melanoma (2,575 cases, 3,241 controls). We adjusted for potential confounding effects of sunlamp use and sunbathing. The magnitude of sunburn associations did not differ significantly by melanoma site, nevus count or histologic subtype of melanoma. Across all sites, relative risk of melanoma increased with an increasing number of reported lifetime "painful" sunburns, lifetime "severe" sunburns and "severe" sunburns in youth (p(trend) < 0.001), with pooled odds ratios (pORs) for the highest category of sunburns versus no sunburns of 3.22 [95% confidence interval (CI) 2.04-5.09] for lifetime "painful" sunburns, 2.10 (95%CI 1.30-3.38) for lifetime "severe" sunburns and 2.43 (95%CI 1.61-3.65) for "severe" sunburns in youth. Solar keratoses strongly increased the risk of head and neck melanoma (pOR 4.91, 95%CI 2.10-11.46), but data were insufficient to assess risk for other sites. Reported sunburn is strongly associated with melanoma on all major body sites.

Nevus density and melanoma risk in women: a pooled analysis to test the divergent pathway hypothesis.

A "divergent pathway" model for the development of cutaneous melanoma has been proposed. The model hypothesizes that melanomas occurring in people with a low tendency to develop nevi will, on average, arise more commonly on habitually sun-exposed body sites such as the head and neck. In contrast, people with an inherent propensity to develop nevi will tend to develop melanomas most often on body sites with large melanocyte populations, such as on the back. We conducted a collaborative analysis to test this hypothesis using the original data from 10 case-control studies of melanoma in women (2,406 cases and 3,119 controls), with assessment of the potential confounding effects of socioeconomic, pigmentary and sun exposure-related factors. Higher nevus count on the arm was associated specifically with an increased risk of melanoma of the trunk (p for trend = 0.0004) and limbs (both upper and lower limb p for trends = 0.01), but not of the head and neck (p for trend = 0.25). The pooled odds ratios for the highest quartile of nonzero nevus count versus none were 4.6 (95% confidence interval (CI) 2.7-7.6) for melanoma of the trunk, 2.0 (95% CI 0.9-4.5) for the head and neck, 4.2 (95% CI 2.3-7.5) for the upper limbs and 3.4 (95% CI 1.5-7.9) for the lower limbs. Aggregate data from these studies suggest that high nevus counts are strongly associated with melanoma of the trunk but less so if at all of the head and neck. This finding supports different etiologic pathways of melanoma development by anatomic site.

A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL).

CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by "blind" exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at the local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.

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 > or =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, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =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 > or =1 patient with MPM and age at diagnosis < or =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.

The prevention, diagnosis, referral and management of melanoma of the skin: concise guidelines.

Melanoma of the skin is an increasingly common tumour, which often has a slow early growth rate during which curable lesions may be detected and removed. Physicians therefore have the potential to reduce mortality and this guideline is intended to promote early diagnosis of melanoma. The majority of melanomas occur in white-skinned people. The most common risk factors are pale sun-sensitive skin and the presence of increased numbers of melanocytic naevi (moles). Melanoma is more common in women than men; the mean age of onset is 50 years; and a fifth of cases occur in young adults. In the UK population the most common sites are on the lower leg in women, and on the back in men. The predictors of melanoma are progressive change in the shape, size and colour of moles. This guideline provides a series of photographs of moles, melanomas and other skin lesions, which may resemble melanomas.

Geographical variation in the penetrance of CDKN2A mutations for melanoma.

BACKGROUND: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium. METHODS: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two-sided. RESULTS: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P =.003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. CONCLUSIONS: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.

Common sequence variants on 20q11.22 confer melanoma susceptibility.

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.

Management of familial melanoma.

Relatives of patients with melanoma are at increased risk of melanoma. We review the evidence that this risk may be attributed both to shared susceptibility genes (both high-penetrance and lower-penetrance genes) and shared environment. The most frequent high-penetrance susceptibility gene is CDKN2A, and environmental effects on the risk to gene carriers are evident in that CDKN2A penetrance is higher in CDKN2A-mutation-positive families living in Australia than those in Europe. We review the approaches to managing melanoma families, in which the likelihood of there being detectable CDKN2A mutations is positively correlated with the number of cases of melanoma in the family. Within families, risk that an individual carries a germline mutation can be estimated by pedigree analysis for autosomal dominant genes with incomplete penetrance. Prevention advice to families relates to moderation of sun exposure and self-examination of naevi, although there are few supportive data.

The genetics of melanoma.

Melanoma is an increasingly common cancer and in order to direct preventative advice at those at risk, an understanding of susceptibility is crucial. This review summarizes what is known about common low-risk genes (such as those controlling red hair) and rare high-risk genes.

Localization of a novel melanoma susceptibility locus to 1p22.

Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.