Search

Vitiligo is the most common cutaneous depigmentation disorder worldwide, yet little is known about specific risk factors for disease development. Using data from the Nurses' Health Study, a prospective cohort study of 51,337 white women, we examined the associations between (i) pigmentary traits and (ii) reactions to sun exposure and risk of incident vitiligo. Nurses' Health Study participants responded to a question about clinician-diagnosed vitiligo and year of diagnosis (2001 or before, 2002-2005, 2006-2009, 2010-2011, or 2012+). We used Cox proportional hazards regression models to estimate the multivariate-adjusted hazard ratios and 95% confidence intervals of incident vitiligo associated with exposures variables, adjusting for potential confounders. We documented 271 cases of incident vitiligo over 835,594 person-years. Vitiligo risk was higher in women who had at least one mole larger than 3 mm in diameter on their left arms (hazard ratio = 1.37, 95% confidence interval = 1.02-1.83). Additionally, vitiligo risk was higher among women with better tanning ability (hazard ratio = 2.59, 95% confidence interval = 1.21-5.54) and in women who experienced at least one blistering sunburn (hazard ratio = 2.17, 95% confidence interval = 1.15-4.10). In this study, upper extremity moles, a higher ability to achieve a tan, and history of a blistering sunburn were associated with a higher risk of developing vitiligo in a population of white women., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

High nevus count is the strongest risk factor for melanoma, and although gene variants have been discovered for both traits, epigenetic variation is unexplored. We investigated 322 healthy human skin DNA methylomes associated with total body nevi count, incorporating genetic and transcriptomic variation. DNA methylation changes were identified at genes involved in melanocyte biology, such as RAF1 (P = 1.2 × 10 -6 ) and CTC1 (region: P = 6.3 × 10 -4 ), and other genes including ARRDC1 (P = 3.1 × 10 -7 ). A subset exhibited coordinated methylation and transcription changes within the same biopsy. The total analysis was also enriched for melanoma-associated DNA methylation variation (P = 6.33 × 10 -6 ). In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 (P = 1.7 × 10 -49 ) and NID1 (P = 6.4 × 10 -14 ), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 × 10 -10 ). Our analysis using a uniquely large dataset comprising healthy skin DNA methylomes identified known and additional regulatory loci and pathways in nevi and melanoma biology. This integrative study improves our understanding of predisposition to nevi and their potential contribution to melanoma pathogenesis., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

A germline polymorphism of the microphthalmia transcription factor (MITF) gene encoding a SUMOylation-deficient E318K-mutated protein has recently been described as a medium-penetrance melanoma gene. In a clinical assessment of nevi from 301 volunteers taken from Queensland, we identified six individuals as MITF E318K mutation carriers. The phenotype for 5 of these individuals showed a commonality of fair skin, body freckling that varied over a wide range, and total nevus count between 46 and 430; in addition, all were multiple primary melanoma patients. The predominant dermoscopic signature pattern of nevi was reticular, and the frequency of globular nevi in carriers varied, which does not suggest that the MITF E318K mutation acts to force the continuous growth of nevi. Excised melanocytic lesions were available for four MITF E318K carrier patients and were compared with a matched range of wild-type (WT) melanocytic lesions. The MITF staining pattern showed a predominant nuclear signal in all sections, with no significant difference in the nuclear/cytoplasmic ratio between mutation-positive or -negative samples. A high incidence of amelanotic melanomas was found within the group, with three of the five melanomas from one patient suggesting a genetic interaction between the MITF E318K allele and an MC1R homozygous red hair color (RHC) variant genotype.

Alcohol has not been linked definitively to non-melanoma skin cancer. We examined whether alcohol intake affects the risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) using data on 54,766 persons enrolled in the prospective Diet, Cancer, and Health cohort. Statistical analyses were based on the Cox proportional hazards model. All hazard ratios (HRs) were multivariate adjusted. Adjustment for exposure to UVR was not possible, but all analyses were adjusted for factors related to susceptibility to UVR, including sun sensitivity, degree of freckling, and number of nevi. A total of 2,409 BCC cases and 198 SCC cases were diagnosed within a median follow-up of 11.4 years. Total current alcohol intake was not associated with BCC risk, but beverage-specific analyses showed an increased BCC risk associated with intake of wine (HR=1.05, 95% confidence interval (CI): 1.02-1.08, current average alcohol intake, per 10 g per day) and spirits (HR=1.11, 95% CI: 1.02-1.21) and a decreased risk with beer (HR=0.97, 95% CI: 0.93-1.00). No convincing associations were found between total alcohol intake and risk for SCC, perhaps because of the limited number of cases. Our findings indicate that alcohol intake may increase the risk for BCC, but the relations seemed to depend on beverage type.

A large number of melanocytic nevi is the strongest known risk factor for melanoma in whites, but its relationship to sun exposure overseas among young white women living in temperate climates is unclear. A total of 754 white English women aged 18-46 years were recruited into a cross-sectional study in 1997-2000 to investigate the effect of ultraviolet exposures on numbers of nevi and atypical nevi, and on skin aging as measured by microtopography. Having ever holidayed in hotter countries was associated with a greater age- and phenotype-adjusted mean number of whole-body nevi (percent increase=74; 95% confidence interval: 24, 144; P=0.001), particularly for holidays taken at ages 18-29 years and for counts of the trunk and lower limbs. Having ever lived overseas was not associated with nevus counts, but was inversely associated with number of atypical nevi (P=0.02). Skin aging was not associated with residence or holidays abroad. The association of holidays overseas with an increased nevus count in young white women, which was stronger in the anatomical sites intermittently exposed to sunlight, supports the hypothesis that intermittent sun exposure is of relevance in the etiology of nevi and, hence, melanoma. The findings are of public health relevance given the growing popularity of foreign holidays.

The risk of cutaneous malignant melanoma (CMM) is strongly associated with total number of nevi. Scanty information is available on the association between CMM at a specific anatomical site and number of nevi at the same site. We analyzed data from a case-control study conducted in Italy between 1992 and 1994, on 542 cases of CMM and 538 hospital controls. Cases and controls were examined by trained dermatologists who counted the number of melanocytic nevi. We derived multivariate odds ratios (ORs) and 95% confidence intervals (95% CIs) of site-specific risk of CMM for high versus low number of nevi at the corresponding site. The ORs of CMM for the highest versus the lowest tertile of number of nevi at the corresponding site was 1.4 (95% CIs: 0.7-2.8) at face and neck, 2.3 (95% CIs: 1.1-4.9) at anterior trunk, 4.9 (95% CIs: 2.9-8.4) at posterior trunk, 2.9 (95% CIs: 1.2-6.6) at upper limbs and 5.0 (95% CIs: 2.9-8.5) at lower limbs. In a case-case analysis, comparing CMM cases at a specific site and CMM cases at all other sites, the only excess risk was found for the posterior trunk, the ORs being 2.1 (95% CIs: 1.2-3.6) for the highest versus the lowest tertile of number of nevi. Our data do not support the hypothesis of a specific effect of nevi at each single anatomical site.

Nevi can approximate the melanoma risk and demographic changes will increase the meaning of signs of skin aging (SSA). However, little is known about the epidemiology of nevi and SSA in the general adult population. We aimed to estimate the prevalence and age distribution of common and atypical nevi and SSA as well as gender differences in a large population-based sample. Within the Cooperative Health Research in the Augsburg Region (KORA) in Germany, a population-based survey was performed. Data were gathered by interview and the number of pigmented lesions and presence of SSA were obtained by dermatological examination. A total of 2,823 adults (mean age 49 years, 50% women) participated (response 67%). Most subjects (60.3%) exhibited 11 to 50 common nevi and 5.2% had at least one atypical nevus. 51.9% were diagnosed with elastosis (Cutis rhomboidalis nuchae, 18.3%; Morbus Favre Racouchot 1.4%). Ephelides were seen in 16%, lentigines solaris in 62.4%, and lentigines seniles in 33.2%. All signs of skin aging increased significantly with age and so did lentigines solaris, seniles, and actinic keratoses. In contrast, common and atypical nevi and ephelides decreased significantly with age. Signs of skin aging are frequent and increase, in contrast to common and atypical nevi, with age.

We report a study of 221 teenage twin pairs to examine the genetic and environmental determinants of nevi representing the most potent phenotypic risk factor for melanoma. Our published heritability analysis estimated that nevi are mainly genetically determined. In this paper we examine the role of sun exposure. We report a correlation between nevus density and sun exposure, particularly that acquired in hotter countries than in the UK (mean nevus density 41 per m2 in those in the highest quartile of exposure vs 24 per m2 in those with no exposure, p<0.0001). We were not able to demonstrate a protective effect for either sun protection cream or shirt wearing. By including phenotypic variables and reported sun exposure into the heritability analysis, we conclude that 66% of the total variance of nevus count is attributable to genetic effects: 7% associated to eye color, 6% to hair color, and 1% to reported skin type, which leaves 52% as to yet unidentified genetic factors. Of the 25% of variation attributable to environmental influences, one-third is estimated to be because of sun exposure on hot holidays.

A common single nucleotide polymorphism (SNP) in the 5' untranslated region (5'UTR) of the epidermal growth factor (EGF) gene modulates the level of transcription of this gene and hence is associated with serum levels of EGF. This variant may be associated with melanoma risk, but conflicting findings have been reported. An Australian melanoma case-control sample was typed for the EGF+61A>G transversion (rs4444903). The sample comprised 753 melanoma cases from 738 families stratified by family history of melanoma and 2387 controls from 645 unselected twin families. Ancestry of the cases and controls was recorded, and the twins had undergone skin examination to assess total body nevus count, degree of freckling and pigmentation phenotype. SNP genotyping was carried out via primer extension followed by matrix-assisted laser desorption time of flight (MALDI-TOF) mass spectroscopy. The EGF+61 SNP was not found to be significantly associated with melanoma status or with development of nevi or freckles. Among melanoma cases, however, G homozygotes had thicker tumors (p=0.05), in keeping with two previous studies. The EGF polymorphism does not appear to predispose to melanoma or nevus development, but its significant association with tumor thickness implies that it may be a useful marker of prognosis.