Sun exposure and host phenotype as predictors of cutaneous melanoma associated with neval remnants or dermal elastosis

Recent research suggests that cutaneous melanomas may arise through 2 distinct pathways, characterized by chronic sun exposure on one hand and nevus-prone phenotype of the host on the other. Two histological characteristics of melanoma consistent with these divergent origins are dermal elastosis in adjacent skin and neval remnants contiguous with the tumor, respectively. To further explore causal heterogeneity in melanoma, we compared sun exposure histories and phenotypic characteristics among a population-based sample of patients newly diagnosed with cutaneous melanoma with and without contiguous neval remnants or dermal elastosis. Tissue blocks were obtained for 141 patients: 53 with superficial spreading melanoma (SSM) of the back, 42 with SSM of head and neck (H & N), and 39 and 7 with lentigo maligna/lentigo maligna melanoma (LM/LMM) of the H & N and back, respectively. Melanomas of the H & N were less likely than those on back to have neval remnants (adjusted OR 0.6, 95% CI 0.3-1.4), but were significantly more likely to have dermal elastosis (adjusted OR 9.3, 95% CI 3.5-25). In site-specific analyses, we found that H & N melanomas with neval remnants were more likely than those without neval remnants to arise in people with more than 60 nevi (adjusted OR 2.1, 95% CI 0.3-14.3), but were less likely to arise in those with more than 20 actinic keratoses. Less marked associations were observed for melanomas of the back. High levels of sun exposure strongly predicted dermal elastosis for H & N melanomas (OR 22.5, 95% CI 2.1-245), but not for melanomas of the back (OR 2.1, 95% CI 0.4-11). We conclude that melanomas with different histologic characteristics have different risk factor profiles, particularly on the head and neck. These data accord with the hypothesis that melanomas arise through different causal pathways.     

Solar elastosis and cutaneous melanoma: A site‐specific analysis

Cutaneous melanomas are postulated to arise through at least two causal pathways, namely the “chronic sun exposure” and “nevus” pathways. While chronic sun exposure probably causes many head/neck melanomas, its role at other sites is unclear. In a population‐based, case‐case comparison study conducted in Brisbane, Australia, we determined the prevalence and epidemiologic correlates of chronic solar damage in skin adjacent to invasive, incident melanomas on the trunk (n = 418) or head/neck (n = 92) among patients aged 18–79 in 2007–2010. Participants self‐reported information about environmental and phenotypic factors, and a dermatologist counted nevi and actinic keratoses. Dermatopathologists assessed solar elastosis adjacent to each melanoma using a four‐point scale (nil, mild, moderate, marked), and noted the presence or absence of adjacent neval remnants. We measured associations between various factors and solar elastosis using polytomous logistic regression. Marked or moderate solar elastosis was observed in 10% and 27%, respectively, of trunk melanomas, and 60% and 17%, respectively, of head/neck melanomas. At both sites, marked elastosis was positively associated with age (p_trend < 0.0001) and inversely associated with neval remnants (p_trend < 0.001). For trunk melanomas, marked elastosis was associated with highest quartiles of total sun exposure [odds‐ratio (OR) = 5.47, 95% confidence interval (CI) = 1.08–27.60] and facial freckling (OR = 2.98, 95% CI = 1.17–7.56), and inversely associated with deeply tanning skin (OR = 0.29, 95% CI = 0.08–1.11) and high nevus counts (OR = 0.08, 95% CI = 0.01–0.66). Mostly similar associations were observed with moderate solar elastosis. About one in three trunk melanomas in Queensland have evidence of moderate‐to‐marked sun damage, and they differ in risk associations from those without.     

Etiologic factors associated with p53 immunostaining in cutaneousmalignant melanoma

Findings from a case-control study of cutaneous malignant melanoma (CMM) in Queensland, Australia, suggest that melanomas exhibiting p53 immunostaining possess different risk factors from those of other melanomas. To further explore this hypothesis, a case-only analysis of risk factors for p53 immunostaining with anti-p53 MAb DO-7 was undertaken in 523 people diagnosed with CMM in Canada and Australia. Phenotypic factors and past sun exposure were measured using a self-administered questionnaire and telephone interview. The presence of strong p53 staining (>10% of cell nuclei positively stained vs. <1% staining) was positively associated with some indicators of high cumulative sun exposure: lentigo maligna melanoma subtype (OR = 3.2 vs. superficial spreading subtype), melanoma location on the head and neck (OR = 2.8 vs. back), histopathologic evidence of solar elastosis (OR = 2.1) and previous diagnosis of nonmelanoma skin cancer (OR = 2.4). Strong staining was negatively associated with high nevus density on the back (OR = 0.2 for >25 nevi vs. 0-3 nevi) and histologic evidence of a coexisting nevus (OR = 0.3). Other factors associated with strong p53 immunostaining include greater Breslow thickness (OR = 7.4 for >4.00 vs. <0.76 mm), male sex (OR = 2.2) and dense freckling (OR = 6.6 vs. few freckles). Of these, thickness, male sex, dense freckling, low nevus density on the back, histologic subtype and history of nonmelanoma skin cancer appeared to be independently associated with strong p53 staining. Our findings are consistent with the Queensland study in suggesting that variables indicating high accumulated sun exposure are positively associated with p53 staining and that an increased number of nevi is positively associated with its absence; they may reflect etiologic and pathogenetic heterogeneity in melanoma.     

Risk associations of melanoma in a Southern European population: results of a case/control study

OBJECTIVES: Limited data exist about the risk factors of melanoma in the Greek population. We investigated the association of melanoma with phenotypic and solar indices in this darker skin population residing in an environment of high ambient ultraviolet radiation. METHODS: Our study included 200 sporadic melanoma cases and 200 age-, sex-matched control subjects. Information on history of sun exposure patterns and cutaneous reaction to sunlight was obtained and a clinical evaluation of pigmentary traits, pigmented lesions, and actinic keratoses was performed. RESULTS: In the multivariate analysis, fair skin (OR: 4.63, for fair skin versus light brown, 95% CI: 1.54-13.92), intermittent sun exposure during childhood (OR: 3.33, >2 weeks/year of sun exposure versus /=10 nevi versus no nevi, 95% CI: 1.65-23.76) and the presence of clinically atypical nevi (OR: 2.84, 95% CI: 1.16-6.98), solar lentigenes were an independent risk factor of melanoma (OR: 4.33, 95% CI: 1.67-11.22). CONCLUSIONS: Intermittent sun exposure of moderate intensity during childhood/adolescence and outdoor leisural activities, in conjunction with a more resistant skin phenotype to acute sunburns and a strong association with nevi and solar lentigenes was a prominent determinant of melanoma risk in our population.     

A case-control study of melanomas of the soles and palms (Australia and Scotland)

Objectives: Because the factors that influence risk of acral melanomas on the soles and palms in White populations are unknown, we investigated these in a multi-center case-control study.Methods: Cases of melanoma of the feet and hands diagnosed from 1987–93 in persons aged over 18 years were ascertained in eastern Australia and western Scotland. There were 275 cases of melanoma on the soles and palms matched to 496 controls (selected from the electoral roll) in Australia, and 36 cases matched to 72 controls (nominated by general practitioners) in Scotland.Results: Acral melanoma was strongly associated with high total body nevus counts (adjusted relative risk [RR]=6.3, 95% confidence interval [CI]=2.5–15.6), and with nevi on the soles (RR=7.5, CI=3.0–18.6). There were also significant positive associations with a penetrative injury of the feet or hands (RR=5.0, CI=3.0–8.6) and with heavy exposure to agricultural chemicals (RR=3.6, CI=1.5–8.3). Sun-sensitive complexions, cumulative sun exposure and a past history of nonmelanoma skin cancer were also associated with increased risk of acral melanoma. Current cigarette smoking was inversely related to acral melanoma (RR=0.6, CI=0.4–0.9).Conclusions: Melanomas of the soles and palms resemble other cutaneous melanomas in their association with sun exposure, but are distinguished from them by their strong positive associations with nevi on the soles, previous penetrative injury, and exposure to agricultural chemicals, and by their inverse association with smoking.     

Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma.

Malignant melanomas often contain BRAF or NRAS mutations, but the relationship of these mutations to ambient UV exposure in combination with phenotypic characteristics is unknown. In a population-based case series from North Carolina, 214 first primary invasive melanoma patients in the year 2000 were interviewed regarding their risk factors. Ambient solar UV exposures were estimated using residential histories and a satellite-based model. Cases were grouped on the basis of BRAF and NRAS somatic mutations, determined using single-strand conformation polymorphism analysis and radiolabeled DNA sequencing, and the risk profiles of these groups were compared. Mutually exclusive BRAF-mutant and NRAS-mutant cases occurred at frequencies of 43.0% and 13.6% with mean ages at diagnosis of 47.3 and 62.1 years, respectively. Tumors from patients with >14 back nevi were more likely to harbor either a BRAF mutation [age-adjusted odds ratio (OR), 3.2; 95% confidence interval (95% CI), 1.4-7.0] or an NRAS mutation (age-adjusted OR, 1.7; 95% CI, 0.6-4.8) compared with patients with 0 to 4 back nevi. However, BRAF-mutant and NRAS-mutant tumors were distinctive in that BRAF-mutant tumors were characteristic of patients with high early-life ambient UV exposure (adjusted OR, 2.6; 95% CI, 1.2-5.3). When ambient UV irradiance was analyzed by decadal age, high exposure at ages 0 to 20 years was associated with BRAF-mutant cases, whereas high exposure at ages 50 and 60 years was characteristic of NRAS-mutant cases. Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure. The association of BRAF mutations with early-life UV exposure provides evidence in support of childhood sun protection for melanoma prevention.     

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. © 2008 Wiley‐Liss, Inc.     

Histologic and epidemiologic correlates of P-MAPK, Brn-2, pRb, p53, and p16 immunostaining in cutaneous melanomas

Histologic, molecular, and epidemiologic data suggest that cutaneous melanomas arise through diverse causal pathways, one of which appears mediated by chronic sunlight exposure, and another associated with a nevus-prone phenotype. To further explore etiologic heterogeneity, we compared expression of key melanoma-related proteins according to histologic characteristics of the tumors and epidemiologic risk factors among a sample of 129 patients newly diagnosed with melanoma. Tumor tissue was stained with antibodies to phospho-mitogen-activated protein kinase (P-MAPK), Brn-2, retinoblastoma protein (pRb), p53, and p16. Using logistic regression analysis, we estimated the odds ratio (OR) and 95% confidence interval (95% CI) of protein expression associated with factors of interest. Except for pRb, candidate protein expression was detected in fewer than half the melanomas examined (P-MAPK, 39%; Brn-2, 30%; p53, 24%; p16, 41%). Strong pRb expression was associated with the presence of >20 solar keratoses (OR 6.5, 95% CI: 1.7-25.1) and melanomas with marked to moderate solar elastosis. p53 expression was positively associated with skin that readily burned (OR 3.8, 95% CI: 0.8-19.0) and was inversely associated with >60 nevi (OR 0.3, 95% CI: 0.04-1.5). Melanomas expressing P-MAPK were more likely to have contiguous neval remnants (OR 2.7, 95% CI: 1.1-6.5). P-MAPK and Brn-2 immunopositive melanomas were >/=4-fold more likely to be of the superficial spreading subtype. Brn-2 and p16 immunopositive melanomas had a greater Breslow thickness than melanomas that did not express these proteins. Brn-2, pRb, and p16 proteins were consistently coexpressed. These findings support the hypothesis that molecular profiles of melanoma reflect their histologic and epidemiologic characteristics, offering further evidence of more than one melanoma causal pathway. Exactly how the expression of each protein relates to the causal pathways needs to be further explored.     

A pooled analysis of melanocytic nevus phenotype and the risk of cutaneous melanoma at different latitudes

An abnormal nevus phenotype is associated with an increased risk of melanoma. We report a pooled analysis conducted using individual nevus data from 15 case-control studies (5,421 melanoma cases and 6,966 controls). The aims were to quantify the risk better and to determine whether relative risk is varied by latitude. Bayesian unconditional logistic random coefficients models were employed to study the risk associated with nevus characteristics. Participants with whole body nevus counts in the highest of 4 population-based categories had a greatly increased risk of melanoma compared with those in the lowest category (pooled odds ratio (pOR) 6.9 (95% confidence interval (CI): 4.4, 11.2) for those aged<50 years and pOR 5.1 (95% CI: 3.6, 7.5) for those aged>or=50). The pOR for presence compared with absence of any clinically atypical nevi was 4.0 (95% CI: 2.8, 5.8). The pORs for 1-2 and >or=3 large nevi on the body compared with none were 2.9 (95% CI: 1.9, 4.3) and 7.1 (95% CI: 4.7, 11.6), respectively. The relative heterogeneities among studies were small for most measures of nevus phenotype, except for the analysis of nevus counts on the arms, which may have been due to methodological differences among studies. The pooled analysis also suggested that an abnormal nevus phenotype is associated most with melanomas on intermittently sun-exposed sites. The presence of increased numbers of nevi, large nevi and clinically atypical nevi on the body are robust risk factors for melanoma showing little variation in relative risk among studies performed at different latitudes.     

BRAF and NRAS mutations in melanoma and melanocytic nevi

In this report, we investigated BRAF/NRAS mutations in samples from a case-control study of melanoma and a series of benign melanocytic nevi. We evaluated potential associations between BRAF mutations and histopathologic and pigmentary characteristics of melanoma. Mutations in BRAF and NRAS were detected by sequencing microdissected/laser-captured DNA from 18 in-situ melanomas, 64 primary melanomas, and 51 nevi. Nevi showed the highest frequency of BRAF mutations (82%). BRAF mutations were identified in 29% of invasive melanomas and in only 5.6% of in-situ melanomas. Mutations in NRAS were found in 5.2% of primary melanomas, 5.9% of nevi and no NRAS mutations were seen in in-situ melanomas. A majority of the BRAF mutations observed in primary invasive melanoma were seen in superficial spreading melanoma (15/17), and melanomas with BRAF mutations were also more likely to be found on a body site that was likely to be exposed to intermittent sun exposure compared with chronic or no sun exposure (P=0.02). Tumors with BRAF mutations were also significantly more likely to occur in association with a contiguous nevus (odds ratio 3.49, 95% confidence interval 1.06-11.46), although a contiguous nevus was not found in all melanomas with a BRAF mutation. Our data support the evidence that the mitogen-activated protein kinase pathway is upregulated in a large percentage of melanocytic lesions, but these mutations are not sufficient for malignant transformation. We suggest that BRAF mutations contribute to benign melanocytic hyperplasia, but are likely to contribute to invasive melanoma only in conjunction with other mutations.     

Early-life sun exposure and risk of melanoma before age 40?years

Objective

To examine associations between early-life sun exposure and risk of invasive cutaneous melanoma diagnosed between ages 18 and 39 years.

Methods

Data were analysed from 606 cases and 481 controls from the Australian Melanoma Family Study, a population-based, case?Ccontrol-family study. Self- and parent-reported sun exposure was collected by interview. Odds ratios (OR) were estimated using unconditional logistic regression, adjusted for potential confounders.

Results

Self-reported childhood total sun exposure was not associated with melanoma overall, but was positively associated with melanoma diagnosed at 18?C29 years of age (OR for highest vs. lowest quartile: 3.21, 95% confidence intervals (CI) 1.38?C7.44; P _trend 0.02; P _interaction by age group 0.09). Analyses restricted to participants whose self-reported sun exposure was concordant with that recalled by their parents gave an OR for the highest versus lowest tertile of childhood total sun exposure of 2.28 (95% CI 1.03?C5.04; P _trend 0.05), and for any versus no severe childhood sunburn of 2.36 (95% CI 1.05?C5.31). The association of self-reported severe sunburn with melanoma was evident only in people who tended to tan rather than burn and in people who had few nevi.

Conclusion

The association of early-life sun exposure with early-onset melanoma is influenced by host factors.     

Melanoma in adolescents: a case-control study of risk factors in Queensland, Australia

The incidence of melanoma increases markedly in the second decade of life but almost nothing is known of the causes of melanoma in this age group. We report on the first population-based case-control study of risk factors for melanoma in adolescents (15-19 years). Data were collected through personal interviews with cases, controls and parents. A single examiner conducted full-body nevus counts and blood samples were collected from cases for analysis of the CDKN2A melanoma predisposition gene. A total of 201 (80%) of the 250 adolescents with melanoma diagnosed between 1987 and 1994 and registered with the Queensland Cancer Registry and 205 (79%) of 258 age-, gender- and location-matched controls who were contacted agreed to participate. The strongest risk factor associated with melanoma in adolescents in a multivariate model was the presence of more than 100 nevi 2 mm or more in diameter (odds ratio [OR] = 46.5, 95% confidence interval [CI] = 11.4-190.8). Other risk factors were red hair (OR = 5.4, 95%CI = 1.0-28.4); blue eyes (OR = 4.5, 95%CI = 1.5-13.6); inability to tan after prolonged sun exposure (OR = 4.7, 95%CI = 0.9-24.6); heavy facial freckling (OR = 3.2, 95% CI = 0.9-12.3); and family history of melanoma (OR = 4.0, 95%CI = 0.8-18.9). Only 2 of 147 cases tested had germline variants or mutations in CDKN2A. There was no association with sunscreen use overall, however, never/rare use of sunscreen at home under the age of 5 years was associated with increased risk (OR = 2.2, 95%CI = 0.7-7.1). There was no difference between cases and controls in cumulative sun exposure in this high-exposure environment. Factors indicating genetic susceptibility to melanoma, in particular, the propensity to develop nevi and freckles, red hair, blue eyes, inability to tan and a family history of the disease are the primary determinants of melanoma among adolescents in this high solar radiation environment. Lack of association with reported sun exposure is consistent with the high genetic susceptibility in this group.     

Melanocytic nevi and sun exposure in a cohort of colorado children: anatomic distribution and site-specific sunburn.

Sun exposure and high prevalence of melanocytic nevi are major risk factors for melanoma, but the relationship between them is not well understood. This study examines the relationship between sun exposure (detailed by anatomic location and history of site-specific sunburns) and the presence of melanocytic nevi on 743 White children in Denver, Colorado. Parental reports of site-specific sunburns were collected annually for 2 years starting at ages 5 to 6 years. In the third year, nevi were counted and mapped by anatomic location. Nevus density was higher for boys (36.0 nevi/m2) than for girls (31.0 nevi/m2; P = 0.04). Nevus density was highest on the face, neck, and lateral forearms and was significantly higher in chronically versus intermittently sun-exposed areas (P < 0.0001). Compared with girls, boys had higher nevus density on the face, neck, and trunk, and lower nevus density on the upper arms and thighs (P < 0.01). In 2 years of reports, most subjects (69%) received at least one sunburn. The face, shoulders, and back were the most frequently sunburned areas of the body. When adjusted for host factors, total number of sunburns was significantly associated with higher total nevus prevalence (P = 0.01 for one burn). Site-specific sunburns were significantly associated with nevus prevalence on the back (P = 0.03 for three or more sunburns), but not on the face, arms, or legs. In this high-risk population, there is evidence for two pathways to nevus accumulation: by chronic sun exposure and by intermittent exposure related to sunburns.     

Occupational sun exposure and risk of melanoma according to anatomical site

Although sunburn and intermittent sun exposures are associated with increased melanoma risk, most studies have found null or inverse associations between occupational (more continuous pattern) sun exposure and melanoma risk. The association of melanoma with occupational sun exposure may differ according to anatomical site, with some studies finding a positive association with melanoma on the head and neck. We examined the association between occupational sun exposure (self‐reported weekday sun exposure) and melanoma risk according to anatomical site, using data from two multicentre population‐based case‐control studies: the Australian Melanoma Family Study (588 cases, 472 controls) and the Genes, Environment and Melanoma study (GEM; 1079 cases, 2,181 controls). Unconditional logistic regression was used to estimate odds ratios (OR) and their 95% confidence intervals, adjusting for potential confounders. Occupational sun exposure was not positively associated with melanoma risk overall or at different body sites in both studies. The GEM study found inverse associations between occupational sun exposure and melanoma on the head and neck [OR for highest vs. lowest quartile: 0.56, 95% confidence intervals (CI) 0.36–0.86, p_trend 0.02], and between the proportion of total sun exposure occurring on weekdays and melanoma on the upper limbs (OR for highest vs. lowest quartile: 0.66, 95% CI 0.42–1.02, p_trend 0.03). Our results suggest that occupational sun exposure does not increase risk of melanoma, even of melanomas situated on the head and neck. This finding seemed not to be due to negative confounding of occupational sun exposure by weekend sun.     

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 D₂ + D₃ 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.     

Factors associated with the prevalence of atypical nevus in a Mediterranean pigmented skin lesion clinic

Atypical melanocytic nevi constitute central risk factor and are precursor lesions for cutaneous melanoma. Data regarding factors associated with their prevalence are mainly derived from fair-skinned populations, whereas little is known regarding their epidemiological associations in darker-skinned, chronically sun-exposed populations. The aim of this study was to identify risk factors for the occurrence of at least one atypical nevus on Crete, the southernmost island of Greece. This hospital-based case-control study included 143 patients and 189 controls with at least one atypical nevus presented at the pigmented skin lesion clinic of the University of Crete. All participants were interviewed and underwent complete skin examination by the same two experienced dermatologists. Multivariate logistic regression analysis was used to adjust for potential confounders. In the multivariate analysis, common melanocytic nevi [odds ratio (OR): of 2.2, 7.5, and 58.9 for the presence of 11-25, 26-100, and >100 common nevi, respectively] and recreational sun exposure (OR: 4.4) increased significantly the risk of the presence of atypical nevus. A decreased risk for atypical nevi was related to an increasing age (OR: 0.96/age), and professional sun exposure (OR: 0.5). Intermittent, recreational sun exposure is mainly associated with the prevalence of atypical nevi in our sample and this effect does not depend on skin phototype. Promotion of sun protection, especially in patients with high numbers of common nevi, might serve as a measure to prevent the development of atypical nevi.     

Constitutional and environmental risk factors for cutaneous melanoma in an Italian population. A case-control study

The aim of this study was to determine the relative risk for cutaneous melanoma associated with phenotypic and environmental variables in a population in central Italy and to assess how the combination of the different risk factors contributes to the overall risk for melanoma. We performed a case-control study of 100 patients with sporadic cutaneous melanoma and 200 controls matched for sex, age, ethnicity and residential area. Individuals were interviewed concerning pigmentary traits and sun exposure, and underwent a total body skin examination. Logistic regression models were used to evaluate the association between cutaneous melanoma and constitutional and environmental variables. The strongest risk factors were prolonged recreational sun exposure (odds ratio [OR] 5.010, 95% confidence interval [CI] 2.110-11.891), the presence of clinically atypical naevi (OR 4.916, 95% CI 2.496-9.995) and the presence of >50 common melanocytic naevi (OR 4.684, 95% CI 2.442-9.231). In addition, occupational sun exposure (OR 2.573, 95% CI 1.399-4.732), light brown hair (OR 2.336, 95% CI 1.328-4.138), high density of solar lentigos and/or actinic keratoses (OR 1.824, 95% CI 1.0-3.510) and type II, fair skin (OR 1.815, 95% CI 1.031-3.193) and blue eyes (OR 1.757, 95% CI 1.0-3.477) were each significantly associated with cutaneous melanoma risk. The combination of individual strong risk factors was associated with up to a 46-fold increase in the risk for cutaneous melanoma. Selected pigmentary traits, sun exposure and melanocytic naevi, individually and in combination, are important risk factors for cutaneous melanoma in an Italian population.     

A theory of site distribution of melanomas: Queensland,Australia

Although sun exposure is believed to be associated causally with cutaneous melanoma, the high incidence on less sun-exposed areas such as the back, as well as on chronically exposed sites such as the face, suggests that the association with sunlight is less straightforward than for other skin cancers. To explain this enigmatic site distribution, a theory of site-dependent susceptibility of melanocytes to malignant transformation is proposed. As possible evidence, all melanomas diagnosed in the state of Queensland, Australia, over a one-year period were surveyed for histologic evidence of benign melanocytic nevus cells adjacent to the melanoma, and analyzed according to anatomic distribution. Results showed a regional variation in the proportion of melanomas with adjacent nevi not explicable by regional variation in nevus density, which suggests that there is a varying susceptibility of nevi to malignant change. Given that nevus cells are equivalent to melanocytes, this finding would support the hypothesis that melanocytes at-large have a differential response to the mitogenic stimulus of sunlight according to anatomic site.     

Genetics of risk factors for melanoma: an adult twin study of nevi and freckles

BACKGROUND: We sought by use of an adult twin study to investigate the relative contribution of genetic and environmental effects on the expression of nevi and freckles, which are known risk factors for melanoma, and to determine if age and sun exposure influence the heritability of nevi. DESIGN AND METHODS: Total nevus and freckle counts were conducted on 127 monozygotic twin pairs and 323 dizygotic twin pairs. Intraclass correlations were calculated by use of analysis of variance. Model-fitting analyses were performed to quantify the genetic and environmental components of the variance for nevus and freckle counts. RESULTS: The intraclass correlation for total nevus counts was.83 in monozygotic pairs compared with.51 in dizygotic pairs. Quantitative genetic analyses showed that the contribution of genetic factors on nevi expression varied according to age. For twins less than 45 years old, the additive genetic variance on total nevus count was 36% (95% confidence interval [CI] = 0.8%-63%), with 38% (95% CI = 14%-61%) and 26% (95% CI = 16%-42%) of the remaining variance attributed to common environment and unique environmental effects, respectively. In twins aged 45 years or older, common environmental effects on total nevus count became negligible, with the additive genetic variance increasing to 84% (95% CI = 77%-88%). Body site was also found to affect the heritability estimates for nevus counts, with a statistically significant difference between sun-exposed and sun-protected sites. The polychoric correlation (i.e., the correlation in liability within twins for more than two categories) for total freckle counts was.91 in monozygotic twin pairs compared with.54 in dizygotic twin pairs. Additive genetic effects explained 91% (95% CI = 86%-94%) of the variance in freckle counts. CONCLUSION: The contribution of genetic factors on the variance for total nevus counts increased with age, and sun exposure appears to influence the expression of nevi. The results of this study highlight the need to take into account the age and site of nevus counts for future genetic linkage or association studies in the search for new melanoma genes.     

MC1R genotype may modify the effect of sun exposure on melanoma risk in the GEM study

We investigated whether MC1R genotype modifies the effect of sun exposure on melanoma risk in 1,018 cases with multiple melanomas (MPM) and 1,875 controls with one melanoma (SPM). There was some suggestion that MC1R genotype modified the effect of beach and water activities on MPM risk: ORs were 1.94 (95% CI 1.40–2.70) for any activities for no R variants and 1.39 (95% CI 1.05–1.84) with R variants (R151C, R160W, D294H, and D84E) (p for interaction 0.08). MC1R modification of sun exposure effects appeared most evident for MPM of the head and neck: for early life ambient UV, the OR was 4.23 (95% CI 1.76–10.20) with no R and 1.04 (95% CI 0.40–2.68) with R (p for interaction = 0.01; p for three-way interaction = 0.01). Phenotype modified the effect of sun exposure and MPM in a similar manner. We conclude that MC1R and pigmentary phenotype may modify the effects of sun exposure on melanoma risk on more continuously sun-exposed skin. Possible explanations include that risk may saturate with higher sun sensitivity for melanomas on continuously sun-exposed sites but continue to increase as sun exposure increases with lower sun sensitivity, or that sun-sensitive people adapt their behavior by increasing sun protection when exposed.