Solar lentigines are strongly related to sun exposure in contrast to ephelides

Solar lentigines and ephelides are different types of pigmented skin lesions predominantly present on sun-exposed skin. Both lesions are risk indicators for melanoma and non-melanoma skin cancer. Solar lentigines are considered as a sign of photodamage although well-conducted epidemiological studies are lacking on this subject. Ephelides are associated with fair skin type and red hair. The aim of the present study was to investigate the relation of sun-exposure estimates with solar lentigines and ephelides. In the Leiden Skin cancer Study 577 patients with malignant melanoma and/or non-melanoma skin cancer and 385 individuals without a history of skin cancer were studied. The presence of solar lentigines and ephelides in the face and on the back was assessed. Data on skin type, hair color, sun-exposure variables and cutaneous signs of photodamage were collected, by questionnaire and physical examination. Data were analyzed by chi-square or Student t-tests and with multivariable regression. Exposure odds ratios with 95% confidence intervals (95% CI) were calculated to estimate the relative risk for the presence of solar lentigines and ephelides dependent on signs of photodamage. The association with age was strongly positive for solar lentigines whereas it was strongly negative for ephelides (P-values for trend <0.0001). After adjustment for age, sex and skin type, solar lentigines on the back were positively associated with cumulative (P = 0.01) and intermittent (P = 0.0002) sun exposure. After adjustment, solar lentigines on the back were also associated with a history of sunburns before the age of 20 yr (P = 0.0003) and the number of sunburns in childhood (P = 0.002). Solar lentigines in the face were significantly associated with cutaneous signs of photodamage, i.e. elastosis (odds ratio 2.4, 95% CI 1.7-3.3) and actinic keratosis (odds ratio 1.8, 95% CI 1.3-2.4) whereas ephelides were not. Ephelides in the face and on the back showed an inverse association with chronic sun exposure but after adjustment theses associations disappeared. Sunburns before the age of 20 appeared to be positively associated with ephelides on the back (P = 0.04). In contrast to lentigines, ephelides were much more associated with constitutional host factors such as fair skin and/or red hair (both P < 0.0001). This study indicates that both chronic and acute sun exposure are important in the pathogenesis of solar lentigines.     

Pigmentation and skin reaction to sun as risk factors for cutaneous melanoma: Western Canada Melanoma Study.

Between 1 April 1979 and 31 March 1981, 904 residents of the four western provinces of Canada (population 6.5 million), were diagnosed as suffering from primary cutaneous malignant melanoma. Of 801 patients aged 20-79 years, 665 (83%) were interviewed along with control subjects chosen at random from the general population and matched for age, sex, and province. After exclusion of 70 subjects with lentigo maligna or acral lentiginous melanoma, comparisons of the 595 case-control pairs showed that light hair, skin, and eye colour, a history of heavy freckling in adolescence, and a tendency to burn readily and tan poorly in the sun were significant risk factors for melanoma. The strongest primary associations were with blond hair (relative risk 7.1 compared with black hair), light colour of unexposed skin (relative risk 2.4), and severe freckling (relative risk 2.1). These associations were independent of ethnic origin and of recorded amount of exposure to the sun and were somewhat stronger for superficial spreading than for nodular melanoma. This study is the largest and most detailed of an incident series of melanomas to be published to date. The results were consistent with other studies reporting associations between melanoma and poor tanning ability, a tendency to burn easily, and a history of sunburn and showed that light hair colour was the strongest risk factor for the disease.     

Childhood exposure to ultraviolet radiation and harmful skin effects: epidemiological evidence

We review the general amount and patterns of exposure to solar ultraviolet (UV) radiation that children and teenagers experience and the spectrum of UV-related skin damage that can occur as a result. Data about the amount of solar UV received by children and teenagers are relatively few but suggest that around 40–50% of total UV to age 60 occurs before age 20. Among white children, those with the palest complexions suffer the most damage. Comparisons of prevalence and incidence of outcomes in children and teenagers sharing common ancestry, but living at different latitudes, show that prevalence rates of photoaging and melanocytic naevi are higher in Australian compared with British children, and similarly for melanoma. Genetic risk for the majority of the melanomas in teens is a function of genes controlling naevus propensity and pigmentation in the skin. High numbers of naevi and freckles, red hair, blue eyes, inability to tan, as well as a family history are the primary determinants of melanoma among adolescents. Beyond the signs of skin damage seen in children are the latent effects observed later in adulthood. Childhood is believed to be a susceptible window for long-term harmful effects of UV, as evidenced by clear differences in skin cancer risk between child and adult migrants from high to low latitudes. Effective UV radiation protection from childhood is necessary to control both immediate and long-term harmful effects on children’s skin.     

Mitochondrial DNA 4977‐base pair common deletion in blood leukocytes and melanoma risk

The 4977‐base pair common deletion DmtDNA4977 is the most frequently observed mitochondrial DNA mutation in human tissues. Because mitochondrial DNA mutations are mainly caused by reactive oxygen species (ROS), and given that oxidative stress plays an important role in melanoma carcinogenesis, the investigation of DmtDNA4977 may be particularly relevant to the development of melanoma. In this study, we compared DmtDNA4977 levels in blood leukocytes from 206 melanoma patients and 219 healthy controls. Overall, melanoma cases had significantly higher levels of DmtDNA4977 than healthy controls (median: 0.60 vs 0.20, P = 0.008). The difference was evident among individuals who were older than 47 yrs, women, and had pigmentation risk factors (e.g., blond or red hair, blue eye, fair skin, light, or none tanning ability after prolonged sun exposure, and freckling in the sun as a child). The difference was also evident among those who had at least one lifetime sunburn with blistering and had no reported use of a sunlamp. Interestingly, among controls, DmtDNA4977 levels differed by phenotypic index and reported use of a sunlamp. In the risk assessment, increased levels of DmtDNA4977 were associated with a 1.23‐fold increased risk of melanoma (odds ratio (OR): 1.23, 95% confidence interval (90% CI): 1.01, 1.50). A significant dose–response relationship was observed in quartile analysis (P = 0.001). In summary, our study suggests that high levels of DmtDNA4977 in blood leukocytes are associated with increased risk of melanoma and that association is affected by both pigmentation and personal history of sun exposure.     

Photo-induced events in the human melanocytic system: photoaggression and photoprotection

The human skin is submitted to solar, essentially ultraviolet radiation (UVR), aggressions, and develops, for sufficient doses, erythema and pigmentation. The individual sun-sensitivity depends on the nature and the quantity of melanins present in the epidermis. These parameters are inherited as genetic traits which account for the large variations of the constitutive and adaptive pigmentation encountered in the caucasian populations. From red-haired skin-sensitive individuals, to dark-haired sun-resistant individuals, phaeomelanins (red) and eumelanins (black) are mixed in variable proportions. Pure melanins extracted from red hairs and black hairs behave differently when submitted to ultraviolet radiations: phaeomelanins develop aggressive species of molecules responsible for DNA damages, mutations, and cell death. On the contrary, eumelanins are less toxic for the major cellular metabolisms. The sun-sensitive populations suffer from more skin cancer of all types than the dark ones. In particular, they are exposed significantly to higher risk of melanoma and to the risk of bearing more nevi following large solar exposures early in the life.     

Actinic skin damage and mortality--the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study

Background

Exposure to sunlight may decrease the risk of several diseases through the synthesis of vitamin D, whereas solar radiation is the main cause of some skin and eye diseases. However, to the best of our knowledge, the association of sun-induced skin damage with mortality remains unknown.

Methodology/Principal Findings

Subjects were 8472 white participants aged 25–74 years in the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Cardiovascular disease mortality, cancer mortality, and all-cause mortality were obtained by either a death certificate or a proxy interview, or both. Actinic skin damage was examined and recorded by the presence and severity (absent, minimal, moderate, or severe) of overall actinic skin damage and its components (i.e., fine telangiectasia, solar elastosis, and actinic keratoses). Cox regression and Kaplan-Meier methods were applied to explore the associations. A total of 672 cancer deaths, 1500 cardiovascular disease deaths, and 2969 deaths from all causes were documented through the follow-up between 1971 and 1992. After controlling for potential confounding variables, severe overall actinic skin damage was associated with a 45% higher risk for all-cause mortality (95% CI: 1.22, 1.72; P<0.001), moderate overall skin damage with a 20% higher risk (95% CI: 1.08., 1.32; P<0.001), and minimal overall skin damage with no significant mortality difference, when compared to those with no skin damage. Similar results were obtained for all-cause mortality with fine telangiectasia, solar elastosis, and actinic keratoses. The results were similar for cancer and cardiovascular disease mortality.

Conclusions

The present study gives an indication of an association of actinic skin damage with cardiovascular disease, cancer and all-cause mortality in white subjects. Given the lack of support in the scientific literature and potential unmeasured confounding factors, this finding should be interpreted with caution. More independent studies are needed before any practical recommendations can be made.     

Epidemiological and clinical characteristics of malignant melanoma in area of West Herzegovina from 1997 to 2010

Incidence rate of cutaneous malignant melanoma (MM), one of the most aggressive skin tumours, is increasing nowadays. Etiology of MM has not been fully understood. Various etiological factors are of relevance for the occurrence of the disease. The solar radiation as well as long term exposure to ultraviolet radiation has the greatest impact on development of this skin tumour. Melanoma risk factors have different associations with melanoma on body sites. This study investigates the epidemiological and clinical characteristics of MM such as age, gender, distribution of MM on the body and type of melanoma in the area of West Herzegovina, on the sample of 205 patients. It presents the occurrence of MM in the period from 1997. to 2010. Both, females and males have increased the risk of melanoma on the trunk (45.9%). Different body sites receive various amounts of sun exposure, yet melanomas occur on all parts of the body. This may represent different pathways in the etiology of melanoma based on body location. The most frequent type of MM was superficial spreading melanoma (SSM) 47.8%. According to our investigation incidence rate was 18.6% (per 1000 patients).     

Pleiotropic and Sex-Specific Effects of Cancer GWAS SNPs on Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study

Background

Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.

Methods

We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.

Results

We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10^-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10^-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e^-4).

Conclusions

We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.     

Mitochondrial DNA Copy Number in Peripheral Blood and Melanoma Risk

Mitochondrial DNA (mtDNA) copy number in peripheral blood has been suggested as risk modifier in various types of cancer. However, its influence on melanoma risk is unclear. We evaluated the association between mtDNA copy number in peripheral blood and melanoma risk in 500 melanoma cases and 500 healthy controls from an ongoing melanoma study. The mtDNA copy number was measured using real-time polymerase chain reaction. Overall, mean mtDNA copy number was significantly higher in cases than in controls (1.15 vs 0.99, P<0.001). Increased mtDNA copy number was associated with a 1.45-fold increased risk of melanoma (95% confidence interval: 1.12-1.97). Significant joint effects between mtDNA copy number and variables related to pigmentation and history of sunlight exposure were observed. This study supports an association between increased mtDNA copy number and melanoma risk that is independent on the known melanoma risk factors (pigmentation and history of sunlight exposure).     

Past exposure to sun,skin phenotype,and risk of multiple sclerosis: case-control study

Objective To examine whether past high sun exposure is associated with a reduced risk of multiple sclerosis.Design Population based case-control study.Setting Tasmania, latitudes 41-3°S.Participants 136 cases with multiple sclerosis and 272 controls randomly drawn from the community and matched on sex and year of birth.Main outcome measure Multiple sclerosis defined by both clinical and magnetic resonance imaging criteria.Results Higher sun exposure when aged 6-15 years (average 2-3 hours or more a day in summer during weekends and holidays) was associated with a decreased risk of multiple sclerosis (adjusted odds ratio 0.31, 95% confidence interval 0.16 to 0.59). Higher exposure in winter seemed more important than higher exposure in summer. Greater actinic damage was also independently associated with a decreased risk of multiple sclerosis (0.32, 0.11 to 0.88 for grades 4-6 disease). A dose-response relation was observed between multiple sclerosis and decreasing sun exposure when aged 6-15 years and with actinic damage.Conclusion Higher sun exposure during childhood and early adolescence is associated with a reduced risk of multiple sclerosis. Insufficient ultraviolet radiation may therefore influence the development of multiple sclerosis.     

Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis

Recent genome-wide association studies (GWAS) identified genetic loci associated with pigmentation, nevi, and skin cancer. We performed a review and meta-analysis of GWAS results, grouping them into four categories: (i) loci associated with pigmentation (hair, eye, and/or skin color), cutaneous UV-response (sun sensitivity and/or freckling), and skin cancer; (ii) loci associated with nevi and melanoma; (iii) loci associated with pigmentation and/or cutaneous UV-response but not skin cancer; and (iv) loci associated distinctly with skin cancer, mostly basal cell carcinoma, but not pigmentation or cutaneous UV-response. These findings suggest at least two pathways for melanoma development (via pigmentation and via nevi), and two pathways for basal cell carcinoma development (via pigmentation and independent of pigmentation). However, further work is necessary to separate the association with skin cancer from the association with pigmentation. As with any GWAS, the identified loci may not include the causal variants and may need confirmation by direct genome sequencing.     

Reviews on sun exposure and artificial light and melanoma

Melanoma is the most common form of cancer among young adults aged 25-29 years and the second most common cancer in those aged 15-29 years. We reviewed all the evidence regarding risk factors for melanoma, looking in particular at childhood exposure to ultraviolet radiation (UV). UV radiation is clearly the predominant environmental and thus potentially modifiable risk factor for melanoma. All activities related to tan-seeking behaviour and history of sunburns were shown to be significantly associated to melanoma. Host factors, such as pigmentary characteristics, and genetic predisposition plays also an important role. UV exposure is not only due to the sun but also to indoor tanning devices that have been shown to lead to an elevated risk of melanoma. The strongest evidence for a link between artificial UV and melanoma is found among individuals who had their first exposure to indoor tanning before the age of 30: they have a 75% increase risk of developing melanoma than individuals who had no exposure to indoor tanning. Prevention is very important, especially for children and young adults, as childhood and adolescence are critical periods in the development of later melanoma. Indoor tanning is a widespread practice in most developed countries, particularly in Northern Europe and the USA. In the recent decades more and more people, especially teenagers and women, are exposed to substantially high radiant exposures of UV through artificial sources and these trends raised a considerable concern. In fact the International Agency for Research on Cancer concluded that the association between skin cancer and exposure to solar radiation and the use of UV-emitting tanning devices are causal. Interesting analyses carried out in Iceland showed that when interventions to discourage sunbed use were introduced the incidence of melanoma among women decreased. All this evidence encouraged many countries to introduce regulations on sunbed use to avoid exposure before the age of 18.     

Residential and occupational exposure to sunlight and mortality from non-Hodgkin's lymphoma: composite (threefold) case-control study.

OBJECTIVE: To determine whether non-Hodgkin''s lymphoma mortality is associated with sunlight exposure. DESIGN: Three case-control studies based on death certificates of non-Hodgkin''s lymphoma, melanoma, and skin cancer mortality examining associations with potential sunlight exposure from residence and occupation. SETTING: 24 states in the United States. SUBJECTS: All cases were deaths from non-Hodgkin''s lymphoma, melanoma, and non-melanotic skin cancer between 1984 and 1991. Two age, sex, and race frequency matched controls per case were selected from non-cancer deaths. MAIN OUTCOME MEASURES: Odds ratios for non-Hodgkin''s lymphoma, melanoma, and skin cancer from residential and occupational sunlight exposure adjusted for age, sex, race, socioeconomic status, and farming occupation. RESULTS: Non-Hodgkin''s lymphoma mortality was not positively associated with sunlight exposure based on residence. Both melanoma and skin cancer were positively associated with residential sunlight exposure. Adjusted odds ratios for residing in states with the highest sunlight exposure were 0.83 (95% confidence interval 0.81 to 0.86) for non-Hodgkin''s lymphoma, 1.12 (1.06 to 1.19) for melanoma, and 1.30 (1.18 to 1.43) for skin cancer. In addition, non-Hodgkin''s lymphoma mortality was not positively associated with occupational sunlight exposure (odds ratio 0.88; 0.81 to 0.96). Skin cancer was slightly positively associated with occupational sunlight exposure (1.14; 0.96 to 1.36). CONCLUSIONS: Unlike skin cancer and to some extent melanoma, non-Hodgkin''s lymphoma mortality was not positively associated with exposure to sunlight. The findings do not therefore support the hypothesis that sunlight exposure contributes to the rising rates of non-Hodgkin''s lymphoma.     

Obesity-related genetic variants, human pigmentation, and risk of melanoma

Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles = 0.12, P value = 4 × 10^?5). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R ² quality metric >0.8 using the 1,000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity.     

UVA, UVB and incidence of cutaneous malignant melanoma in Norway and Sweden

Latitudinal dependencies of UVA and UVB were studied together with relevant epidemiological data for squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM) in Norway and Sweden. Our data support the hypothesis that solar UVA radiation may play a role for CMM induction. The etiologies of SCC and CMM are different according to a latitudinal dependency and differences in age curves. Sun exposure patterns, age-related decay rates of repair of UV damage and sex hormones may play different roles for the two skin cancers. Also, UVB induction of vitamin D may be involved. CMM incidence rates among young people have decreased or been constant since about 1990 in Norway and Sweden. All reasons for UVA contributing to CMM will be discussed.     

Long-term histologic follow-up of phenol face peels

Deep phenol peels were done on 11 middle-aged white women with severe actinic damage. Subsequently, face lifts were carried out after periods of 1.5 to 20 years. This made it possible to obtain a full-thickness specimen extending several centimeters on either side of the border between peeled and unpeeled skin. In contrast to the markedly abnormal elastotic appearance of unpeeled skin, a new band of connective tissue 2 to 3 mm in width was laid down in the subepidermal region. Fine elastic fibers formed a dense network in the band of regenerated collagen. The disarray and cytologic abnormalities of sun-damaged epidermis were also largely corrected. Melanocytes were not eliminated, but melanin synthesis was evidently impaired, accounting for the bleaching effects. The effects of a phenol peel are very long lasting and adequately account for the effacement of wrinkles and obliteration of actinic keratoses, mottling, and freckling.     

The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes

We have examined melanocortin-1 receptor (MC1R) variant allele frequencies in the general population and in a collection of adolescent dizygotic and monozygotic twins to determine statistical associations of pigmentation phenotypes with increased skin cancer risk. This included hair and skin color, freckling, mole count and sun exposed skin reflectance. Nine variants were studied and designated as either strong R (OR = 63; 95% CI 32-140) or weak r (OR = 5; 95% CI 3-11) red hair alleles. Penetrance of each MC1R variant allele was consistent with an allelic model where effects were multiplicative for red hair but additive for skin reflectance. To assess the interaction of the brown eye color gene BEY2/OCA2 on the phenotypic effects of variant MC1R alleles we imputed OCA2 genotype in the twin collection. A modifying effect of OCA2 on MC1R variant alleles was seen on constitutive skin color, freckling and mole count. In order to study the individual effects of these variants on pigmentation phenotype we have established a series of human primary melanocyte strains genotyped for the MC1R receptor. These include strains which are MC1R wild-type consensus, variant heterozygotes, and homozygotes for strong R alleles Arg151Cys and Arg160Trp. Ultrastructural analysis demonstrated that only consensus strains contained stage III and IV melanosomes in their terminal dendrites whereas Arg151Cys and Arg160Trp homozygous strains contained only immature stage I and II melanosomes. Such genetic association studies combined with the functional analysis of MC1R variant alleles in melanocytic cells should provide a link in understanding the association between pigmentary phototypes and skin cancer risk.     

Current opportunities and challenges: genome-wide association studies on pigmentation and skin cancer

Genome-wide association studies (GWAS) have become a widely used approach for genetic association studies of various human traits. A few GWAS have been conducted with the goal of identifying novel loci for pigmentation traits, melanoma, and non-melanoma skin cancer. Nevertheless, the phenotype variation explained by the genetic markers identified so far is limited. In this review, we discuss the GWAS study design and its application in pigmentation and skin cancer research. Furthermore, we summarize recent developments in post-GWAS activities such as meta-analysis, pathway analysis, and risk prediction.     

Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?

Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.     

Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data

Acquired melanocytic nevi (MN) in Caucasian populations are important markers for the risk of melanoma development. The total number of MN on the whole body is the most important independent risk factor for melanoma and the risk of melanoma development increases almost linearly with rising numbers of MN. Additionally, the presence of atypical MN and of actinic lentigines are likewise independent risk factors for melanoma. Atypical mole syndrome should be defined by the presence of many acquired MN and a threshold number of atypical MN. Acquired MN develops mainly during childhood and adolescence in the first two decades of life. The number of acquired nevi seems to be related to hereditary factors and nevus-prone families exist. The amount of sun exposure is the most important environmental risk factor for nevus development, particularly in early childhood. Interestingly, sunburns may play a role in nevus development, but seem not to be required, and even moderate sun exposure promotes the process. Therefore, preventive measures for nevus and melanoma development should target young children and adolescents.