Adapted from Gerstenblith et al. (2010). A double plus sign (++) indicates a signiﬁcant association (P < 10-7) in GWAS. A single plus sign (+) indicates an association (P between 0.01 and 10-7). A minus sign (-) indicates a null association (P > 0.01). A blank cell indicates that the locus in the left column has not been not tested. BCC=basal cell carcinoma. SCC =squamous cell carcinoma.
Epidemiological evidence is overwhelming that exposure of the skin to ultraviolet radiation (UVR) can increase one’s risk of developing malignant melanoma. However the situation is complex, as melanoma development is associated with “intermittent” sun exposure, whereas epidermal keratinocyte-based skin cancers like squamous cell carcinoma (SCC) are associated with chronic UVR exposure. Thus it is difficult to talk in terms of a classical UVR carcinogenic mechanism for melanoma in general. Melanoma risk seems intricately associated with pigmentation characteristics. Genome wide association studies identify variants in genes involved in pigmentation as risk factors, generally the strongest signal being for the melanocortin receptor 1 gene (
2. Epidemiology of melanoma
One atypical naevus (RR 1.60, CI 1.4-1.8)
Five or more atypical naevus (RR 10.5, CI 5.1-21.5).
Multiple banal melanocytic naevi - 100 vs <15 (RR-6.9, CI 4.6-10.3).
Red versus dark hair (RR 3.6, CI 2.5-5.4).
Sunburns in childhood (RR 2.2, CI 1.73-2.89
Sunburns in adulthood (RR 1.9, CI 1.6-2.7)
Chronic sun exposure (RR 1.0, CI 0.8-1.1)
Apart from familial predisposition, the strongest risk factor for the development of cancer generally, the presence of naevi, especially dysplastic naevi, is the innate, or phenotypic factor that most increases the probability of developing a melanoma. Sunlight is the only environmental factor that has been consistently implicated as a cause of melanoma, leading to a melanoma incidence 10- to 20- fold higher among fair-skinned than dark-skinned peoples (Armstrong & Kricker, 1993). Among fair-skinned people, melanoma incidence increases with proximity to the equator and several studies have shown that fair-skinned migrants moving from high (e.g. UK) to low latitude countries (e.g. Australia, South Africa) have lower melanoma rates than native-born residents (Whiteman and Green, 1999; Khlat et al., 1992; Mc Credie et al., 1990; Mc Michael and Giles, 1988). Individuals with xeroderma pigmentosum (XP), a disorder in which sufferers have a gene mutation that diminishes their ability to repair UVR-induced DNA damage, have much higher risk of melanoma than the population average (Kraemer et al., 1994; Cleaver, 2006). Those with a past history of non-melanoma skin cancer (caused by high exposures to solar UVR) have a 3-fold higher risk of melanoma than the general population (Green et al., 1993).
3. Genetic basis of melanoma
3.1. Genes involved in familial melanoma susceptibility
Although many different genes can be somatically mutated in melanoma, as yet there are only two confirmed familial melanoma susceptibility loci,
3.2. Genes associated with melanoma in genome wide association studies
Genome wide association (GWA) studies have been used to discover genes that confer risk for skin cancer development (Table 1). Some genes are associated both melanoma and non-melanoma skin cancer, especially basal cell carcinoma (BCC). Five genes associated with melanoma,
MC1R, melanoma risk and sun exposure
The mechanism by which the carriage of
4. The epidemiological association between sunlight and melanoma is complex
Despite the persuasive descriptive evidence linking sunlight with melanoma, several observations make clear that the association is complex and does not accord with a simple model in which the risk of melanoma increases directly with increasing levels of exposure to the sun. Melanoma occurs more commonly among indoor than outdoor workers (Beral & Robinson, 1981). Even in sunny countries most melanomas develop on sites that are habitually covered by clothing (such as the back), as opposed to sites more frequently exposed to the sun such as the face (Green et al., 1993). Many case-control studies of melanoma incidence report stronger associations with intermittent (short periods of intense sun exposure to untanned skin) rather than chronic patterns of sun exposure (Elwood & Jopson, 1997). Recreational sun exposure is a risk factor for melanoma on the trunk and limbs but not on the head and neck (Chang et al., 2009).
Chronic sun exposure and a “classical” UVR carcinogenic mechanism involving UVB-induced DNA damage is accepted to be responsible for the development of SCC. One reason frequently proposed for the lack of association of melanoma with chronic sun exposure is that there may be a different carcinogenic mechanism for melanoma, possibly involving UVA exposure. The potential role of UVA in the induction of melanoma has been reviewed elsewhere (e.g. Wang et al., 2001; Moan et al., 2008; Godar et al. 2009). Sunlight at different latitudes contains vastly different rations of UVA/UVB, with a greater proportion of UVB nearer the equator, and less closer to the poles. Because the change in melanoma incidence with latitude is much smaller than that for SCC (which is dependent upon cumulative UVB exposure) it is hypothesized that UVA play a role at least in exacerbating the development of melanoma (Godar et al., 2009; Wang et al., 2010). Other ideas revolve around the notion that office workers are at higher relative risk possibly due excessive UVA that can penetrate glass (Godar et al., 2009). Further, recreational exposure, generally agreed to increase melanoma risk, can include solarium use. Depending on the lamp type used, artificial tanning devices (sunbeds or solariums) emit higher UVA/UVB ratios and possibly higher UVA doses than found in sunlight (Miller et al., 1998; Gerber et al., 2002). A meta-analysis of nineteen studies has shown that exposure to sunbeds at a young age is the most damaging, with a relative risk for “first exposure under the age of 35” of 1.75 (95% CI, 1.35, 2.26) (International Agency for Research on Cancer Working group on artificial UV light and skin cancer, 2007). A large prospective cohort study of 106,366 women in Sweden and Norway showed that solarium use at ages 30-39 linked to a relative risk of 1.49 (95% CI, 1.11-2.00)(Veierod et al., 2011). Thus epidemiological evidence suggests that sunbeds are health hazards in terms of melanoma risk and that UVA has a plausible role in the development of this neoplasm. Hence epidemiological data is somewhat supportive of the view that the full UVR spectrum may be carcinogenic in melanoma. It should be noted that at any point on the earth it is difficult to precisely predict the UVA/UVB ratio in sunlight as it can greatly vary with time of day, altitude, latitude and climate factors (De Fabo et al., 2004).
5. Naevus and melanoma subtypes
From the point of view of basic biology differences between melanoma and non-melanoma skin cancer in terms of their relationship with UVR exposure is not surprising. Melanocytes are long living cells, resistant to apoptosis, whose principal function is to produce melanin. In contrast, the primary function of keratinocytes is to provide a protective barrier, the epidermis, which is in a continual state of regeneration, supplied by proliferation of epidermal basal layer keratinocytes that initiates a programmed process of differentiation and apoptosis as needed. Melanocytes can undergo a form of proliferation, where they form senescent groups, or nests, which are termed naevi. Such lesions are negative for proliferation markers, but can progress to malignancy, albeit at an extremely low frequency (Grichnik, 2008). There are multiple subtypes of naevi. These include dermal (blue naevi), compound (common acquired, spitz and congenital naevi) and epidermal (e.g. reed naevi) lesions (Grichnik, 2008). These subtypes may be influenced differently by UVR exposure, and there may be differences in their propensities for transformation (e.g. which is probably much less for dermal naevi). Hence the subtype of naevus can be a confounding factor when studying environmental and genetic factors influencing naevo genesis. For instance the positive association between naevus count and
Likewise there are several major melanoma subtypes, and then subtle forms within each group. Superficial spreading melanoma (SSM) is the most common form in Caucasians (around 70% of all melanomas). It follows a radial growth phase with atypical melanocytes, either as single cells or nests at all levels of the epidermis (Smoller, 2006), followed by an invasive vertical growth phase. Nodular melanoma (NM) are primary dermal lesions characterized by growth through the dermis, generally lack epidermal involvement, and a very sharply circumscribed with virtual lack of radial spread (Smoller, 2006). Lentigo maligna melanoma (LMM) is the only subtype unequivocally associated with chronic sun exposure. Lesions display confluent spread of melanocytes along the epidermal basal layer and in the upper portion of the hair follicle and are invariably associated with solar elastosis in adjacent skin (Smoller, 2006). SMM and NM, but not LMM, sometimes have naeval remnants present on histopathology. Acral lentiginous and mucosal melanomas are epidermal lesions that occur on palmoplantar and mucosal surfaces respectively, and are assumed not to be influenced by UVR exposure. Clearly, any discussion of the effects of chronic versus intermittent sun exposure has to consider melanoma subtype.
6. The divergent pathway model of melanoma
To assess the effects of chronic versus intermittent sun exposure melanomas have been stratified into chronic sun damage (CSD) or non-chronic sun damage (non-CSD) melanomas, either histologically by assessing solar elastosis, a measure of chronic exposure (e.g. Curtin et al., 2005), or by comparing melanomas developing on the head and neck (an anatomical region of high cumulative sun exposure), and the trunk (a region of intermittent exposure). While these two methods of classification may create some confounding differences, overall the use of either system supports the conclusion of a complex relationship between melanoma and sun exposure that has lead to the proposal of a “divergent pathway” model (Whiteman et al., 2003). According to this model (Figure 1) the pathways diverge after an initial insult that stabilizes the melanocyte. This may be early life exposure to UVR given that childhood sunburns are a risk factor for melanoma (Whiteman et al., 2001). What happens thereafter depends upon a combination of host characteristics and subsequent patterns and doses of UVR exposure. Melanomas that develop on the head and neck are associated with solar elastosis (a marker of CSD), low naevus count, and relatively late age of onset. In contrast, melanomas developing on the trunk via the intermittent UVR (non-CSD) pathway tend to have relatively earlier age of onset and are associated with higher naevus count.
Several studies have published findings concordant with the divergent pathway hypothesis (Carli and Palli, 2003; Chang et al., 2009; Bataille et al., 1998). Given the strong association between truncal (non-CSD) melanomas and naevus development, and the fact that most naevi carry
7. Stratification of CSD and non-CSD melanomas by innate phenotypic and genetic variation
7.1. MC1R variants
Landi et al. (2006) reported that individuals in Italian and U.S. cohorts that developed
7.2. Genes controlling the development of naevi
Given that the “intermittent” exposure arm of the divergent pathway is associated with the presence of naevi, we should be able to obtain clues about how to differentiate the pathways based on genes that confer naevus risk. Naevi are benign proliferations of melanocytes, and the number of naevi individuals tend to develop is under strong genetic control (English & Armstrong, 1994; Harrison et al., 1994). Monozygotic, or identical twin pairs, share all genes and have extremely highly correlated naevus counts (twin1 vs twin2, r=0.94), whereas dizygotic twin pairs share on average only half of their genes, and their naevus counts are considerably less correlated (r=0.60) (Zhu et al., 1999). The great majority naevi carry the
The number of naevi an individual develops does not appear to just an innate trait, it may also be associated with levels of sun exposure, especially in children (reviewed in Gallagher et al., 1995; Bauer et al., 2003). Recent studies examining the association of holidays overseas among young white English women found an increased in naevus count, particularly on anatomical sites intermittently exposed to sunlight, supporting the hypothesis that intermittent sun exposure is of relevance in the aetiology of naevi (Silva Idos, et al., 2009).
7.3. UVR-induced proliferation of melanocytes
Of possible relevance is how the branches of the divergent pathways differ in terms of the propensity of melanocytes in the skin to proliferate after UVR. Early studies in humans demonstrated that melanocyte density was correlated with sun exposure (Mitchell, 1963; Staricco & Pinkus, 1957; Stierner et al., 1989). Work by Quevedo and Colleagues (1965) reported that in mice melanocyte density increased up to 4-fold following repeated UVR exposure, possibly due to increased mitotic activity of melanocytes (Rosdahl, 1978). More recent experiments have shown that melanocyte proliferation is greater following exposure to UVB than UVA, and that a single dose has a substantially greater effect than the same dose fractionated over several days (An et al., 2001; van Schanke et al., 2005). The generation of melanoma in mouse models using neonatal UVR is usually, although not always, accompanied by a strong proliferative response of melanocytes and their migration to the burnt area of the skin (Walker et al., 2009; Ferguson et al., 2010). Melanocyte proliferation would seem to be linked to the tanning response, which increases the amount of pigment in the skin, and is driven by UVB-induced damage to the skin. This is akin to “delayed tanning”, that can occur 1-5 d after exposure, and is primarily due to increased melanin production, although multiple exposures induce proliferation of melanocytes resulting in increased numbers in human skin (Yamaguchi et al., 2008). This is a long lasting protective pigmentation, unlike UVA-induced intermediate pigment darkening (IPD), which results from oxidation of pre-existing melanin, fades quickly, and is not protective against subsequent exposures. Interestingly, the induction of active melanocytes in mouse skin is also produced by chemical carcinogens, and the more carcinogenic the compound the greater the tanning response (Iwata et al., 1981). Liver carcinogens that are not metabolically activated in skin are ineffective. The compound most effective in inducing melanocyte proliferation was 7,12-dimethylbenz[a]anthracene (DMBA), a very potent skin carcinogen. Thus the response of melanocytes is driven either by UVR or compounds that induce adducts within the DNA of skin cells.
Melanocyte proliferation after UVR is thought to be driven by cytokines released by the microenvironment (Figure 2). UVR exposure modulates the production by keratinocytes (and probably other cells) of endothelins, Kit ligand (KITL), fibroblast growth factors (FGFs), and many others, which are all regulate melanocyte function (Hirobe, 2005; Lin & Fisher, 2007; Imokawa, 2004). These include α-MSH (alpha melanocyte stimulating hormone), ACTH and a range of other growth factors. α-MSH and ACTH both bind to the MC1R on the surface of melanocytes, which activates the cyclic-AMP dependent kinase pathway, and the production of melanin pigments and possibly melanocyte proliferation. Most of these signaling molecules are known to enhance pigmentation, but little is known about how they might influence melanocyte proliferation
7.4. Stratification of CSD and non-CSD by somatic mutations signatures
Examination of melanomas of various subtypes by array comparative genome hybridization (CGH) has detected significant differences at specific genomic locations such that DNA copy number differences could stratify melanomas into CSD, non-CSD, acral and mucosal melanomas (the latter two assumed not associated with sun exposure)(Curtin et al., 2005). Subsequently the same group detected activating mutations of KIT in 28% (n=18) of CSD melanomas versus 0% (n=18). This raised hopes that KIT mutation status may differentiate CSD and non-CSD melanomas, but a subsequent Australian publication (Handolias et al., 2010) showed that the frequency of
8. Vitamin D and potential protective effects of chronic sun exposure on melanoma?
Vitamin D has been shown to inhibit proliferation and induce differentiation in some melanoma cells, although melanoma cell lines have demonstrated resistance to vitamin D growth arrest (Danielsson et al., 1998,1999; Reichrath et al., 2007). A population-based study of 528 melanoma cases found that the presence of solar elastosis (dermal sun damage) was associated with a better prognosis for melanoma patients (Berwick et al., 2005). These findings have provoked speculation that as chronic sun damage induces a less aggressive form of melanoma (LMM), perhaps vitamin D levels might somehow slow melanoma growth and/or improve prognosis. To further determine if the anti-proliferative effect of vitamin D is modifying outcome for melanoma patients, Downing and colleagues, (2008) carried out a study to compare two populations with similar ethnic background but potentially different environmental influences. Patients diagnosed with invasive melanoma between 1993 and 2003 in Yorkshire (n= 4170) and New South Wales (NSW, n= 30,520) were identified from cancer registry databases and prognostic information (age, sex, socioeconomic background, tumour site and Breslow thickness) was examined. Five-year relative survival was 86.9% (95% CI, 85.2-88.5) in Yorkshire and 88.6% (95% CI, 88.1-89.1) in NSW. There was a suggestion of reduced risk for death in Australia, but differences in tumour thickness appeared to be the most important factor. The difference in survival may be due to the strong health promotion message for screening of skin cancer in Australia resulting in increased detection of early thin lesions with better outcomes. A recent follow-up study of 872 patients from the Leeds cohort (median follow-up, 4.7 years) has shown that higher 25-hydroxyvitamin D3 levels, at diagnosis, were associated with both thinner tumours and better survival from melanoma, independent of Breslow thickness (Newton-Bishop et al., 2009). This data needs to be validated in additional sample sets and the level of vitamin D in the follow up period examined. Understanding the balance between optimal sun exposure to limit skin cancer risk while maintaining adequate vitamin D levels has been further complicated by work from Damian et al. (2010), which found that vitamin D had a presumably undesirable immunosuppressive effect when vitamin D analogues were applied topically to irradiated skin. On the other hand, Mason et al. (2010) reported that increased vitamin D levels reduced DNA damage
9. Animals as model systems for melanoma
To mechanistically link sun exposure and melanoma is very difficult because individual sun exposure, especially based on recall, is difficult to assess, and the ratio of UVB/UVA varies greatly with geographical location, season, and time of day. This leads to great uncertainty in inferences about how different wavelengths influence melanoma development, hence sometimes model experimental systems can be useful, and animal models for carcinogenesis can provide complementary information when epidemiological studies have difficulty avoiding confounding factors. Grey horses and certain strains of pig are models for genetic susceptibility to melanoma, although there is no evidence for any effects of UVR exposure (Rosengren Pielberg et al., 2008; Seltenhammer et al., 2004). Opossom, guinea pigs and Angora goats have also been used as models for melanocytic lesion development (Chan et al., 2001; Menzies et al., 2004; Green et al., 1996). However except for goats, UVR exposure is not known to play any role in melanoma development in these animals. All of these species are very expensive to maintain, and generally limited in terms of the availability of reagents such as antibodies, and resources for genetic analyses. Various strains of fish including zebrafish (reviewed by Patton et al., 2010) and other fish species such as
9.1. Modeling chronic-induced melanoma in mice
In contrast to the ability to induce SCC in wild type mice using chronic treatment regimens, a pre-existing genetically engineered mutation, and exposure of neonates, is necessary for inducing murine melanoma (Noonan et al., 2001). There are three reasons proposed to explain why mice develop melanoma after neonatal UVR, but not after chronic exposures to adult animals. First, neonatal mice have epidermal melanocytes that are likely to be damaged by UVR, whereas adult mice do not. Second, the heightened sensitivity of neonatal melanocytes to proliferation following UVR may be destabilizing (Walker et al., 2009), and third, the lack of inflammatory response to UVR in neonates may create a tolerant environment for melanocyte transformation (Wolnicka-Glubisz et al., 2007; Mc Gee et al., 2011). It is thought that murine neonatal UVR may be somewhat analogous to childhood sunburn (Noonan et al., 2001). Despite it being a somewhat specialized system, there is much we can learn using the neonatal UVR about how UVR results in melanocyte transformation. For instance using the
The skin of hairless mice contains some epidermal melanocytes, hence the animals represent a murine system amenable to chronic UVR exposures. Van Schanke et al. (2006) have carried out extensive UVR carcinogenesis studies on such animals carrying
In terms of using adult mice for UVR studies, a major problem is that they do not have epidermal melanocytes (and murine melanomas that develop are mostly dermal). Mice overexpressing Kitl in their keratinocytes (
10. Mechanisms of UVR carcinogenesis in melanoma
10.1. Evidence of UVB causality in melanoma
The ultraviolet spectrum that plays a physiological role in skin cancer development is arbitrarily divided into UVB (280-315 nm) and UVA 315-400 nm). Non-melanoma skin cancer (especially SCC) is undeniably associated with chronic UVR exposure, and tumours carry “classical” UVB signature mutations resulting from mis-repaired cyclobutane pyrimidine dimer (CPD) or pyrimidine (6-4) pyrimidone photoproducts (6-4 PPs) adducts. The action spectrum for SCC induction in mice, and the inferred action spectrum for SCC in humans, peaks at 293 nm, firmly within the UVB range (de Gruijl et al., 1993). This overlaps with the action spectrum for CPD formation and sunburn. UVB, but not UVA, very effectively induces non-melanoma and melanoma skin cancer in mice (De Gruijl et al., 1993; De Fabo et al., 2004). Evidence of a critical role for UVB in melanoma induction comes from humans (van Steeg & Kramer, 1999) and mice (Yang et al., 2007) carrying nucleotide excision repair (NER) enzyme mutations (in
More information about the melanoma UVR mutation signature comes from the first melanoma genome sequence (Pleasance et al., 2010). Of 33,000 single point mutations detected, nearly 70% were C-T transitions. The only other nucleotide change above levels expected by chance were G-T transitions (9%) that can be a marker for UVA-induced damage (Agar et al., 2004). Notwithstanding the fact that only one melanoma, a secondary with undetected primary, was sequenced (Pleasance et al., 2010), and that some mutations could have been acquired by sun exposure during tumour development, these results suggest that CPD adducts may be critical driver of melanoma genesis. This is remarkably similar to the results of a recent review of all known
Although we usually concentrate on CPDs as the mutagenic adduct, UVB also induces 6-4PPs, which are larger the CPDs, hence recognized and removed much more rapidly by nucleotide excision repair (NER). It has been hypothesized that 6-4PPs may be involved in melanoma induction, not via a mutagenic mechanism, rather via their deregulation of genome surveillance and transcription mechanisms leading to downstream changes that may deregulate the melanocyte (Mitchell et al., 2010). It is known that the two forms of UVB-induced photoproduct induce differential effects within cells (Lo et al., 2005). 6-4PP lesions are much more important in triggering cell death, whereas the response of the cell to CPD lesions mainly involves cell cycle arrest. An important role for 6-4PPs in melanoma is a speculative but interesting potential alternate aetiogy. Of note, 6-4PPs play no role in the generation of SCC in mice, CPD adducts are necessary and sufficient (Jans et al., 2005).
10.2. Evidence of UVA causality in melanoma
In contrast to UVB, UVA is generally extremely inefficient at inducing CPDs, oxidative damage, erythema, and non-melanoma skin cancer in mice (De Gruijl et al., 1993; Besaratinia & Pfeifer, 2008; Runger & Kappes, 2008). However UVA can induce 8-oxo-guanine (8-oxoG) oxidative adducts that can results in the formation of G-T transversions (Agar et al., 2004). Results of another study suggest that T-G transversion is a UVA “signature” (Drobetsky et al., 1995). UVA-specific lesions in the p53 gene have been detected in skin constructs and squamous tumours (Agar et al., 2004; Huang et al., 2009). In contrast,
Notably, most of the studies mentioned above have used keratinocytes and fibroblasts, and not melanocytes to assess the mutagenicity of UVA. A recent study suggests that UVA is much more effective than UVB in inducing reactive oxygen species in melanocytes than in the other cell types (Wang et al., 2010). In addition, melanocytes are less efficient in removing CPDs and oxidative DNA damage. As discussed by Runger, (2011), these findings are at odds with some other studies, but nonetheless are indicative of potential differences between the responses of melanocytes and other skin cells to UVR. Runger, (2011) also raises the question of why if there is so much oxidative damage induced by UVA why are lesions typical for such stress vastly underrepresented in melanoma (e.g. Pleasance et al., 2010)? He suggests that this could relate to the low mutagenicity of 8-oxoG adducts.
The ability of UVA to generate melanoma in
One would expect that if melanin sensitization were an important mechanism, we would not see the huge increase in melanoma risk for patients with XP, unless they also lacked a defence against the melanin radicals.However there remains an anomaly that Africans with albinism (i.e. no melanin, or low levels), who practice poor sun protection, have been consistently shown to only very rarely develop melanoma (reviewed in Wood et al., 2006). In 164 such patients in Tanzania actinic keratoses were found in 100%, and SCC in 34%, of albino individuals over 30 years old, but no melanomas were found (Lookingbill et al., 1995). In these cases childhood sunburns do not seem to drive subsequent melanoma development.
The only other model used as evidence for UVA causality in melanoma is the South American opossum,
It must be pointed out that the murine and fish studies cannot model cumulative lifetime exposure to UVA in sunlight. We cannot rule out a role for UVA given that although the genotoxicity (i.e. frequency of dimers) is much higher in the UVB, UVA is far more abundant in sunlight (at least 20-fold). Not only are there debates about the role of UVA, there are even studies suggesting a protective role for UVA. Here, with UVB dose kept constant, increasing UVA dose protects against epidermal apoptosis (Ibuki et al., 2007) and SCC induction in mice (Forbes et al., 1978). Which wavelengths are critical for melanoma formation? In some ways this is irrelevant, and the real question is what type of adducts are needed? The balance of evidence to date suggests that the susceptibility of a melanocytes to UVR-induced transformation depends mostly upon the presence of classical CPD type adducts that if not properly removed result in C-T or CC-TT mutations. However this has not been formally proven.
10.3. Role of UVR in generating
BRAF and NRAS mutations
The DNA base changes causing activating mutations in
It is difficult to glean much from murine melanoma models regarding the potential role of UVR in inducing
As suggested by Runger, (2011), oncogenes can only function as such due to very specific gain-of-function mutations that can only occur as certain amino acid changes, “
11. UVR, melanoma, and the immune system
There is undoubtedly an interplay between damaged melanocytes and immunocytes, whether just after UVR exposure or during tumour progression. It has long been known that the UVR exposure can suppress the immune system and create an environment tolerant to the growth of tumour cells that should be targeted for immunological destruction. Margaret Kripke and colleagues (Donawho et al., 1996) described how the growth of implanted tumours in mice is enhanced by local photoimmunosuppression. How much of a role it plays in melanoma development is unknown. Transplant patients taking immunosuppressive drugs are at a particularly heightened risk of skin cancer, particularly SCC, but it is a matter of debate whether they are at increased risk of melanoma. Out of nine studies recently reviewed (Bastiaannet et al., 2007), five reported between 2 and 4-fold increased risk, and four reported no increased risk. If immunosuppressed patients are at increased melanoma risk, it is low, and much less than the risk of developing SCC. Despite this, individuals taking immunosuppressive drugs sometimes develop eruptive naevi, and this form of melanocyte proliferation is proposed to be due to the effects of immunosuppression rather than the drugs that induce it (Zattra et al., 2009).
An important factor in the initiation of melanoma in mice by neonatal and not adult exposure is that neonates exhibit a defective inflammatory response to UVR compared to adults (Wolnicka-Glubisz et al., 2007; Mc Gee et al., 2011). There may be ways to investigate the role that photoimmunosuppression plays in UVR-induced tumorigenesis. For example, (Jans et al. 2005) used mice carrying an inducible photolyase system that very rapidly removes CPDs from the skin after UVR exposure. Removal of CPDs from the whole skin significantly reduces both SCC development and immunosuppression. However, removal of CPDs specifically from the epidermal basal layer (using
11.2. UVR-induced inflammation
One of the difficulties in studying UVR causality in melanoma is not only that multiple UVR response mechanisms such as DNA repair, proliferation and immune response play a role, but they are often not independent of each other. We can look at the normal response of melanocytes to UVR (Figure 2), in particular the multiple effects of cytokines that are released in the skin to activate melanocytes. Upon UVR-induced damage keratinocytes upregulate their expression of the pro-opiomelanocortin (Pomc) gene. Pomc encodes a pro-peptide that is cleaved to generate α-MSH, ACTH and β-endorphin (Cui et al., 2007). Together, these peptides have pleiotropic effects on endocrine and neuroendocrine signaling, and the immune system (Brzoska et al., 2008), in addition to the melanotropic function of αMSH. Another protein upregulated in the epidermis after UVR exposure, KITL, can drive proliferation and migration of both pro-inflammatory mast cells as well as melanocytes (Kunisada et al., 1998). Pro-inflammatory cytokines like interleukin 12 (Schwarz et al., 2002) and interleukin-18 (Schwarz et al., 2006) can increase DNA repair capability of melanocytes after UVR exposure. In the case of interleukin-18, this may be via upregulation of KITL (Hue et al., 2005). Another secreted protein, previously known only for its role in immune responses to infectious agents, β-Defensin, is upregulated over 50-fold in human epidermis after UVR exposure (Enk et al., 2006) and is possibly involved in melanocye response to UVR as another ligand for the MC1R (Candille et al., 2007). Thus the release of cytokines within the skin not only activates the immune system, but also induces protective responses in the melanocye itself (e.g. increased pigmentation, proliferation, and DNA repair).
The proliferative burst of melanocytes emanating from the upper portion of the hair follicle in neonatal mice presents an excellent opportunity to investigate how melanocytes are activated by UVR exposure. Zaidi et al. (2011) have cleverly utilized the power of the genetically modified mice to look into the mechanism of this melanocyte response. They used a genetically engineered mouse model inducibly expressing green fluorescent protein (GFP) in melanocytes. GFP was induced immediately after UVB exposure and melanocytes were isolated via fluorescence activated cell sorting at various time-points after neonatal UVR. Gene expression array analysis on these cells detected a strong signature of interferon-gamma (IFNγ)-induced genes that coincided with the appearance of melanocytes in the epidermis. It was subsequently shown that that the melanocyte response is largely driven by IFNγ released from infiltrating macrophages. Further experiments indicated that not only can macrophages influence melanocyte proliferation in the context of UVR exposure, but that they also contribute to the pro-tumorigenic inflammatory microenvironment of melanomas. This is possibly the first study to establish a direct link between the immune and melanocytic systems during the immediate skin response to UVR.
Because, measured on a population basis, melanoma induction by UVR appears to be via a very different mechanism (i.e. via intermittent exposure) than for keratinocyte-derived cancers (i.e. via chronic exposure), it has been postulated that there are different carcinogenic mechanisms at play (Setlow, 1999). Different mutagenic DNA adducts are proposed to be involved, including UVA-induced oxidative lesions, UVB-induced pyrimidine dimers and 6-4PPs. In studies of human populations individual sun exposure level, based on recall, can be difficult to assess, but also the ratio of UVB/UVA varies greatly with geographical location, season, and time of day. This leads to uncertainty in inferences about how much exposure and which wavelengths most influence melanoma development. However epidemiological work has lead to the proposal of the divergent pathway model for melanoma, where some melanomas develop as a result of intermittent exposure, others after chronic exposures (Whiteman et al., 2003). The major difference between the chronic and intermittent branches of the model is the presence of naevi, the great majority of which carry
If multiple carcinogenic mechanisms are at play, this can be tested in a number of ways. The stratification of melanomas into CSD and non-CSD has been critical in enhancing our understanding of divergent mechanisms of melanoma genesis, but since the two major forms of melanoma, SSM and NM can be associated with either forms of exposure, further stratification may be necessary (Of note, LMM clearly has a different aetiology from NM and SSM). This may be in the form of the discovery of better somatic mutation signatures, as well as further innate genetic differences between the two groups. The development of further tests to differentiate between the two groups could help in terms of targeting particularly susceptible groups within the population for health education campaigns and more frequent screening. High throughput genome sequencing of large numbers of melanomas of various subtypes and association with CSD or non-CSD should clarify which type of DNA adducts are driving melanoma development, and in doing so might go some way towards clarifying the role of UVB versus UVA in the genesis of melanoma. Improved animals models should also be informative.
Of necessity we have had to be somewhat selective and we apologize to colleagues whose work we have not discussed. G.W. is funded by a Queensland Cancer Council Senior Research Fellowship. E.H is funded by a National Health and Medical Research Fellowship.
Abdel-Malek Z. A. Ruwe A. Kavanagh-Starner R. Kadekaro A. L. Swope V. Haskell-Luevano C. Koikov L. Knittel J. J. 2009alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes. , 22 5 635 44
Agar N. S. Halliday G. M. Barnetson R. S. Ananthaswamy H. N. Wheeler M. Jones A. M. 2004The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis. , 101 14 4954 9
An H. T. Yoo J. Y. Lee M. K. Sin M. H. Rhie G. E. Seo J. Y. Chung J. H. Eun H. C. Cho K. H. 2001Single dose radiation is more effective for the UV-induced activation and proliferation of melanocytes than fractionated dose radiation. , 17 266 71
Armstrong B. K. Kricker A. 1993How much melanoma is caused by sun exposure? , 3 395 401
Baldea I. Mocan T. Cosgarea R. 2009The role of ultraviolet radiation and tyrosine stimulated melanogenesis in the induction of oxidative stress alterations in fair skin melanocytes. , 31 4 200 8
Bataille V. Grulich A. Sasiseni P. Swerdlow A. Newton Bishop. J. Mc Carthy W. Hersey P. Cuzick J. 1998The association between naevi and melanoma in populations with different levels of sun exposure: a joint case-control study of melanoma in the UK and Australia. , 77 505 10
Bastiaannet E. Homan-van der Heide. J. J. Ploeg R. J. Hoekstra H. J. 2007No increase of melanoma after kidneytransplantation in the northern part of The Netherlands. Melanoma Res, 17 6 349 53
Bauer J. Garbe C. 2003Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data. 16 3 297 306
Beaumont K. A. Shecker S. N. Newton R. A. James M. R. Stow J. L. Duffy D. L. Sturm R. A. 2007Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. , 16 2249 60
Beral V. Robinson N. 1981The relationship of malignant melanoma, basal and squamous skin cancers to indoor and outdoor work. , 44 886 91
Berking C. Takemoto R. Satyamoorthy K. Shirakawa T. Eskandarpour M. Hansson J. Van Belle P. A. Elder D. E. Herlyn M. 2004Induction of melanoma phenotypes in human skin by growth factors and ultraviolet B. 64 3 807 11
Besaratinia A. Pfeifer G. 2008Sunlight ultraviolet radiation and BRAF 600mutagenesis in human melanoma. , 29, 8, 993-991.
Berwick M. Armstrong B. K. Ben-Porat L. Fine J. Kricker A. Eberle C. Barnhill R. 2005Sun exposure and mortality from melanoma, 97 195 9
Böhm M. Wolff I. Scholzen T. E. Robinson S. J. Healy E. Luger T. A. Schwarz T. Schwarz A. 2005alpha-Melanocyte-stimulating hormone protects from ultraviolet radiation-induced apoptosis and DNA damage. , 280 7 5795 802
Box N. F. Wyeth J. R. O’Gorman L. E. Martin N. G. Sturm R. A. 1997Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair. 6 1891 7
Brenner M. Coelho S. G. Beer J. Z. Miller S. A. Wolber R. Smuda C. Hearing V. J. 2009Long-lasting molecular changes in human skin after repetitive in situ UV irradiation. , 129 1002 11
Broome Powell. M. Gause P. R. Hyman P. Gregus J. Lluria-Prevatt M. Nagle R. Bowden G. T. 1999Induction of melanoma in TPras transgenic mice. , 20 9 1747 53
Brzoska T. Luger T. A. Maaser C. Abels C. Böhm M. 2008Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. , 29 5 581 602
Candille S. I. Kaelin C. B. Cattanach B. M. Yu B. Thompson D. A. Nix M. A. Kerns J. A. Schmutz S. M. Millhauser G. L. Barsh G. S. 2007A β-defensin mutation causes black coat color in domestic dogs. , 318 5855 1418 23
Cardones A. Grichnik J. M. 2009Melanocyte-Stimulating Hormone-Induced Eruptive Nevi. 145 4 441 444
Carli P. Palli D. 2003Re: Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. , 95, 1801.
Carrera C. Puig S. Llambrich A. Palou J. Lecha M. Massi D. Malvehy J. 2008Development of a human in vivo method to study the effect of ultraviolet radiation and sunscreens in melanocytic nevi. , 217 2 124 36
Chan J. Robinson E. S. Atencio J. Wang Z. Kazianis S. Coletta L. D. Nairn R. S. Mc Carrey J. R. 2001Characterization of the CDKN2A and ARF genes in UV-induced melanocytic hyperplasias and melanomas of an opossum (Monodelphis domestica). , 31 1 16 26
Chang Y. M. Barrett J. H. Bishop D. T. Armstrong B. K. Bataille V. Bergman W. Berwick M. Bracci P. M. Elwood J. M. Ernstoff M. S. Gallagher R. P. Green A. C. Gruis N. A. Holly E. A. Ingvar C. Kanetsky P. A. Karagas M. R. Lee T. K. Le Marchand L. Mackie R. M. Olsson H. Østerlind A. Rebbeck T. R. Sasieni P. Siskind V. Swerdlow A. J. Titus-Ernstoff L. Zens M. S. Newton-Bishop J. A. 2009Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls. I, 38 814 30
Cleaver J. E. 2006The biology of xeroderma pigmentosum. In Hearing, V. (Ed.) From . 291 310Totowa, N.J, Humana Press.
Cohen C. Zavala-Pompa A. Sequeira J. H. Shoji M. Sexton D. G. Cotsonis G. Cerimele F. Govindarajan B. Macaron N. Arbiser J. L. 2002Mitogen-actived protein kinase activation is an early event in melanoma progression. , 8 3728 33
Costin G. E. Hearing V. J. 2007Human skin pigmentation: melanocytes modulate skin color in response to stress. , 21 4 976 94
Cui R. Widlund H. R. Feige E. Lin J. Y. Wilensky D. L. Igras V. E. D’Orazio J. Fung C. Y. Schanbacher C. F. Granter S. R. Fisher D. E. 2007Central role of 53in the suntan response and pathologic hyperpigmentation. , 128, 5, 853-64.
Curtin J. A. Busam K. Pinkel D. Bastian B. C. 2006Somatic activation of KIT in distinct subtypes of melanoma, 24 4340 6
Curtin J. A. Fridlyand J. Kageshita T. Patel H. N. Busam K. J. Kutzner H. Cho K. H. Aiba S. Brocker E. B. Leboit P. E. Pinkel D. Bastian B. C. 2005Distinct sets of genetic alterations in melanoma. , 353 2135 47
Cust A. E. Harland M. Makalic E. Schmidt D. Dowty J. G. Aitken J. F. Agha-Hamilton C. Armstrong B. K. Barrett J. H. Chan M. Chang Y. M. Gascoyne J. Giles G. G. Holland E. A. Kefford R. F. Kukalizch K. Lowery J. Randerson-Moor J. A. Schmid H. Taylor C. F. Whitaker L. Hopper J. L. Newton-Bishop J. A. Mann G. J. Bishop D. T. Jenkins M. A. 2010Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK. [Epub ahead of print].
Damian D. L. Kim Y. J. Dixon K. M. Halliday G. M. Javeri A. Mason R. S. 2010Topical calcitriol protects from UV-induced genetic damage but suppresses cutaneous immunity in humans. , 19, e 23 30
Danielsson C. Fehsel K. Polly P. Carlberg C. 1998Differential apoptotic response of human melanoma cells to 1 alpha,25-dihydroxyvitamin D3 and its analogues. , 5 946 52
Danielsson C. Torma H. Vahlquist A. Carlberg C. 1999Positive and negative interaction of 1 25dihydroxyvitamin D3 and the retinoid CD437 in the induction of human melanoma cell apoptosis. , 81, 467-70.
De Fabo E. C. Noonan F. P. Fears T. Merlino G. 2004Ultraviolet B but not ultraviolet A radiation initiates melanoma. , 64 18 6372 6
de Gruijl F. R. Sterenborg H. J. Forbes P. D. Davies R. E. Cole C. Kelfkens G. van Weelden H. Slaper H. van der Leun J. 1993Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice. 53 1 53 60
Domen N. Marais R. 2007New insights into BRAF mutations in cancer. 17 1 31 39
Donawho C. K. Muller H. K. Bucana C. D. Kripke M. L. 1996Enhanced growth of murine melanoma in ultraviolet-irradiated skin is associated with local inhibition of immune effector mechanisms. J Immunol, 157 2 781 6
Downing A. Yu X. Q. Newton-Bishop J. Forman D. 2008Trends in prognostic factors and survival from cutaneous melanoma in Yorkshire, UK and New South Wales, Australia between 1993 and 2003. , 123 861 6
Duffy D. L. Iles M. M. Glass D. Zhu G. Barrett J. H. Höiom V. Zhao Z. Z. Sturm R. A. Soranzo N. Hammond C. Kvaskoff M. Whiteman D. C. Mangino M. Hansson J. Newton-Bishop J. A. Geno M. E. L. Bataille V. Hayward N. K. Martin N. G. Bishop D. T. Spector T. D. Montgomery G. W. 2010variants have age-specific effects on nevus count and predispose to melanoma. Am J Hum Genet 87 1 6 16
Drobetsky E. A. Turcotte J. Châteauneuf A. 1995A role for ultraviolet A in solar mutagenesis. , 92 6 2350 4
Edlundh-Rose E. Egyhazi S. Omholt K. Mansson-Brahme E. Platz A. Hansson J. Lundberg J. 2006NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. , 16 471 8
Elwood J. M. Jopson J. 1997Melanoma and sun exposure: an overview of published studies. , 73 198 203
English D. R. Armstrong B. K. 1994Melanocytic nevi in children. I. Anatomic sites and demographic and host factors. , 139 390 401
Enk C. D. Jacob-Hirsch J. Gal H. Verbovetski I. Amariglio N. Mevorach D. Ingber A. Givol D. Rechavi G. Hochberg M. 2006The UVB-induced gene expression profile of human epidermis in vivo is different from that of cultured keratinocytes. , 25 18 2601 14
Falchi M. Bataille V. Hayward N. K. Duffy D. L. Bishop J. A. Pastinen T. Cervino A. Zhao Z. Z. Deloukis P. Soranzo N. Elder D. E. Barrett J. H. Martin N. G. Bishop D. T. Montgomery G. W. Spector T. D. 2009Genome-wide association study identifies variants at 9 21and 22q13 associated with development of cutaneous nevi. , 41, 915-9.
Fargnoli M. C. Pike K. Pfeiffer R. M. Tsang S. Rozenblum E. Munroe D. J. Golubeva Y. Calista D. Seidenari S. Massi D. Carli P. Bauer J. Elder D. E. Bastian B. C. Peris K. Landi M. T. 2008MC1R variants increase risk of melanomas harboring BRAF mutations. , 128 2485 90
Ferguson B. Muller H. K. Handoko H. Y. Khosrotehrani K. Beermann F. Hacker E. Soyer H. P. Bosenberg M. Walker G. J. 2010Differential roles of the pRb and Arf/ 53pathways in murine naevus and melanoma genesis. , 23, 6, 771-80.
Fitch K. R. Mc Gowan K. A. van Raamsdonk C. D. Fuchs H. Lee D. Puech A. Hérault Y. Threadgill D. W. Hrabé de Angelis. M. Barsh G. S. 2003Genetics of dark skin in mice. Genes Dev, 17(2), 214-28.
Fisher D. Barnhill R. Hodi F. S. Herlyn M. Merlino G. Medrano E. Bastian B. Landi T. M. Sosman J. 2009Melanoma from bench to bedside: meeting report from the 6th international melanoma congress. , 23 14 26
Fisher D. Barnhill R. Hodi F. Herlyn M. Merlino G. Medrano E. Bastian B. Landi T. Sosman J. 2009Melanoma from bench to bedside: meeting report from the 6th international melanoma congress. , 23 1 14 26
Forbes P. D. Davies R. E. Urbach F. 1978Experimental ultraviolet photocarcinogenesis: wavelength interactions and time-dose relationships. , 50 31 8
Gallagher R. P. Mc Lean D. I. 1995The epidemiology of acquired melanocytic nevi. A brief review. 13 3 595 603
Gandini S. Sera F. Cattaruzza M. S. Pasquini P. Picconi O. Boyle P. Melchi C. F. 2005aMeta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. . 41 1 45 60
Gandini S. Sera F. Cattaruzza M. S. Pasquini P. Abeni D. Boyle P. Melchi C. F. 2005bMeta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. , 41 1 28 44
Gerber B. Mathys P. Moser M. Bressoud D. Braun-Fahrlander C. 2002Ultraviolet emission spectra of sunbeds. , 76 664 668
Gerstenblith M. R. Shi J. Landi M. T. 2010Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis. , 23 5 587 606
Godar D. E. Landry R. J. Lucas A. D. 2009Increased UVA exposures and decreased cutaneous Vitamin D3 levels may be responsible for the increasing incidence of melanoma. , 72 434 443
Goldstein A. M. Struewing J. P. Chidambaram A. Fraser M. C. Tucker M. A. 2000Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. , 92 12 1006 10
Green A. Maclennan R. Youl P. Martin N. 1993Site distribution of cutaneous melanoma in Queensland. , 53 232 6
Green A. Neale R. Kelly R. Smith I. Ablett E. Meyers B. Parsons P. 1996An animal model for human melanoma. , 64 3 577 80
Grichnik J. M. 2008Melanoma, nevogenesis, and stem cell biology.J Invest Dermatol, 128(10), 2365-80.
Hacker E. Hayward N. K. 2008Germline MC1R variants and BRAF mutant melanoma. , 128 2354 6
Hacker E. Hayward N. K. Dumenil T. James M. R. Whiteman D. C. 2010aThe association between MC1R genotype and BRAF mutation status in cutaneous melanoma: findings from an Australian population, 130 241 8
Handolias D. Salemi R. Murray W. Tan A. Liu W. Viros A. Dobrovic A. Kelly J. Mc Arthur G. A. 2010Mutations in KIT occur at low frequency in melanomas arising from anatomical sites associated with chronic and intermittent sun exposure. 23 2 210 5
Harrison S. L. Maclennan R. Speare R. Wronski I. 1994Sun exposure and melanocytic naevi in young Australian children. , 344 1529 32
Hauser J. E. Kadekaro A. L. Kavanagh R. J. Wakamatsu K. Terzieva S. Schwemberger S. Babcock G. Rao M. B. Ito S. Abdel-Malek Z. A. 2006Melanin content and MC1R function independently affect UVR-induced DNA damage in cultured human melanocytes. , 19 4 303 14
Hill H. Z. 1992The function of melanin or six blind people examine an elephant. 14 1 49 56
Hirobe T. 2005Role of keratinocyte-derived factors involved in regulating the proliferation and differentiation of mammalian epidermal melanocytes. , 18 1 2 12
Hocker T. Tsao H. 2007Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. , 28 6 578 88
Huang X. X. Bernerd F. Halliday G. M. 2009Ultraviolet A within sunlight induces mutations in the epidermal basal layer of engineered human skin. , 174 4 1534 43
Hue J. Kim A. Song H. Choi I. Park H. Kim T. Lee W. J. Kang H. Cho D. 2005IL-18 enhances SCF production of melanoma cells by regulating ROI and 38MAPK activity. , 96, 2, 211-7.
Ibuki Y. Allanson M. Dixon K. M. Reeve V. E. 2007Radiation sources providing increased UVA/UVB ratios attenuate the apoptotic effects of the UVB waveband UVA-dose-dependently in hairless mouse skin. , 127 9 2236 44
Imokawa G. 2004Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders. . 17 2 96 110
International Agency for Research on Cancer Working Group on artificial ultraviolet (UV) light and skin cancer. 2007The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: A systematic review. , 120 5 1116 22
Iwata K. Inui N. Takeuchi T. 1981Induction of active melanocytes in mouse skin by carcinogens: a new method for detection of skin carcinogens. , 2 7 589 93
Jans J. Schul W. Sert Y. G. Rijksen Y. Rebel H. Eker A. P. Nakajima S. van Steeg H. de Gruijl F. R. Yasui A. Hoeijmakers J. H. van der Horst G. T. 2005Powerful skin cancer protection by a CPD-photolyase transgene. , 15 2 105 15
Kadekaro A. L. Kavanagh R. Kanto H. Terzieva S. Hauser J. Kobayashi N. Schwemberger S. Cornelius J. Babcock G. Shertzer H. G. Scott G. Abdel-Malek Z. A. 2005Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. , 65 10 4292 9
Kanetsky P. A. Panossian S. Elder D. E. Guerry D. Ming M. E. Schuchter L. Rebbeck T. R. 2010Does MC1R genotype convey information about melanoma risk beyond risk phenotypes? , 116 10 2416 28
Khlat M. Vail A. Parkin M. Green A. 1992Mortality from melanoma in migrants to Australia: variation by age at arrival and duration of stay. , 135 1103 13
Kielbassa C. Roza L. Epe B. 1997Wavelength dependence of oxidative DNA damage induced by UV and visible light. , 18 4 811 6
Klug H. Tooze J. A. Graff-Cherry C. Anver M. Noonan F. Fears T. R. Tucker M. De Fabo E. Merlino G. 2010Sunscreen prevention of melanoma in man and mouse. , 23 6 835 7
Kraemer K. H. Lee M. M. Andrews A. D. Lambert W. C. 1994The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. The xeroderma pigmentosum paradigm. , 130 1018 21
Kunisada T. Lu S. Z. Yoshida H. Nishikawa S. Nishikawa S. Mizoguchi M. Hayashi S. Tyrrell L. Williams D. A. Wang X. Longley B. J. 1998Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor. , 187 10 1565 73
Landi M. T. Bauer J. Pteiffer R. M. Elder D. E. Hulley B. Minghetti P. Calista D. Kanetsky P. A. Pinkel D. Bastian B. C. 2006MC1R germline variants confer risk for BRAF-mutant melanoma. , 313 521 2
Langan E. A. Ramlogan D. Jamieson L. A. Rhodes L. E. 2009Change in moles linked to use of unlicensed "sun tan jab". 338, b277.
Lee J. H. Choi J. W. Kim Y. S. 2010Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. [Epub ahead of print].
Ley R. D. 2001Dose response for ultraviolet radiation A-induced focal melanocytic hyperplasia and nonmelanoma skin tumors in Monodelphis domestica. , 73 1 20 3
Lin J. Y. Fisher D. E. 2007Melanocyte biology and skin pigmentation. , 445 843 50
Lo H. L. Nakajima S. Ma L. Walter B. Yasui A. Ethell D. W. Owen L. B. 2005Differential biologic effects of CPD and 6 4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest. 19, 5, 135.
López-Rovira T. Silva-Vargas V. Watt F. M. 2005Different consequences of beta1 integrin deletion in neonatal and adult mouse epidermis reveal a context-dependent role of integrins in regulating proliferation, differentiation, and intercellular communication. , 125 6 1215 27
Lookingbill D. P. Lookingbill G. L. Leppard B. 1995Actinic damage and skin cancer in albinos in northern Tanzania: findings in 164 patients enrolled in an outreach skin care program. , 32 4 653 8
Lund L. P. Timmins G. S. 2007Melanoma, long wavelength ultraviolet and sunscreens: controversies and potential resolutions. , 114 2 198 207
Mason R. S. 2010Vitamin D: a hormone for all seasons. , 14 197 203
Mattei S. Colombo M. P. Melani C. Silvani A. Parmiani G. Herlyn M. 1994Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. , 56 853 7
Mc Credie M. Coates M. S. Ford J. M. 1990Cancer incidence in migrants to New South Wales from England, Wales, Scotland and Ireland. , 62 992 5
Mc Gee H. M. Malley R. C. Muller H. K. Woods G. M. 2011Neonatal exposure to UVR alters skin immune system development, and suppresses immunity in adulthood. , [Epub ahead of print].
Mc Gowan K. A. Li J. Z. Park C. Y. Beaudry V. Tabor H. K. Sabnis A. J. Zhang W. Fuchs H. de Angelis M. H. Myers R. M. Attardi L. D. Barsh G. S. 2008Ribosomal mutations cause 53dark skin and pleiotropic effects. , 40, 8, 963-70.
Mc Michael A. J. Giles G. G. 1988Cancer in migrants to Australia: extending the descriptive epidemiological data. , 48 751 6
Menzies S. W. Greenoak G. E. Abeywardana C. M. Crotty K. A. O’Neill M. E. 2004UV light from 290 to 325 nm, but not broad-band UVA or visible light, augments the formation of melanocytic nevi in a guinea-pig model for human nevi. , 123 2 354 60
Michaloglou C. Vredeveld L. C. Soengas M. S. Denoyelle C. Kuilman T. Van Der Horst C. M. Majoor D. M. Shay J. W. Mooi W. J. Peeper D. S. 2005BRAFE600-associated senescence-like cell cycle arrest of human naevi. , 436 720 4
Mitchell R. E. 1963The Effect of Prolonged Solar Radiation on Melanocytes of the Human Epidermis. , 41 199 212
Mitchell D. Paniker L. Sanchez G. Trono D. Nairn R. 2007The etiology of sunlight-induced melanoma in Xiphophorus hybrid fish. , 46 8 679 84
Mitchell D. L. Fernandez A. A. Nairn R. S. Garcia R. Paniker L. Trono D. Thames H. D. Gimenez-Conti I. 2010Ultraviolet A does not induce melanomas in a Xiphophorus hybrid fish model. , 107 20 9329 34
Mitchell D. L. Fernandez A. A. 2011Different types of DNA damage play different roles in the etiology of sunlight-induced melanoma. , 24 1 119 24
Miller S. A. Hamilton Wester S. L. U. G. Cyr W. H. 1998An analysis of UVA emissions from sunlamps and the potential importance for melanoma. Photochem Photobiol, 68(1), 63-70.
Moan J. Porojnicu A. C. Dahlback A. 2008Ultraviolet radiation and malignant melanoma. Adv Exp Med Biol, 624 104 16
Mouret S. Baudouin C. Charveron M. Favier A. Cadet J. Douki T. 2006Cyclobutane pyrimidine dimers are predominant DNA lesions in whole human skin exposed to UVA radiation. , 103 37 13765 70
Newton-Bishop J. A. Beswick S. Randerson-Moor J. Chang Y. M. Affleck P. Elliot F. Chan M. Leake S. Karpavicius B. Haynes S. Kukalizch K. Whitaker L. Jackson S. Gerry E. Nolan C. Bertram C. Marsden J. Elder D. E. Barrett J. H. Bishop D. T. 2009Serum 25-hydroxyvitamin D3 levels are associated with breslow thickness at presentation and survival from melanoma. , 27 5439 44
Noonan F. P. Recaio J. A. Takayama H. Duray P. Anver M. R. Rush W. L. De Fabo E. C. Merlino G. 2001Neonatal sunburn and melanoma in mice. , 413 271 2
Patton E. E. Mitchell D. L. Nairn R. S. 2010Genetic and environmental melanoma models in fish. , 23 3 314 37
Platz A. Egyhazi S. Ringborg U. Hansson J. 2008Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. 1 4 395 405
Pleasance E. D. Cheetham R. K. Stephens P. J. Mc Bride D. J. Humphray S. J. Greenman C. D. Varela I. Lin M. L. Ordóñez G. R. Bignell G. R. Ye K. Alipaz J. Bauer M. J. Beare D. Butler A. Carter R. J. Chen L. Cox A. J. Edkins S. Kokko-Gonzales P. I. Gormley N. A. Grocock R. J. Haudenschild C. D. Hims M. M. James T. Jia M. Kingsbury Z. Leroy C. Marshall J. Menzies A. Mudie L. J. Ning Z. Royce T. Schulz-Trieglaff O. B. Spiridou A. Stebbings L. A. Szajkowski L. Teague J. Williamson D. Chin L. Ross M. T. Campbell P. J. Bentley Futreal D. R. P. A. Stratton M. R. 2010A comprehensive catalogue of somatic mutations from a human cancer genome. , 463 7278 191 6
Peters G. 2008Tumor suppression for ARFicionados: the relative contributions of 16INK4aand p14ARF in melanoma. 100, 11, 784-95.
Platz A. Egyhazi S. Ringborg U. Hansson J. 2008Human cutaneous melanoma; a review of and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol Oncol, 1 4 395 405
Pollock P. M. Harper U. L. Hansen K. S. Yudt L. M. Stark M. Robbins C. M. Moses T. Y. Hostetter G. Wagner U. Kakareka J. Salem G. Pohida T. Heenan P. Duray P. Kallioniemi O. Hayward N. K. Trent J. M. Meltzer P. S. 2003High frequency of BRAF mutations in nevi. , 33 19 20
Quevado W. C. Jr Szabo G. Virks J. Sinesi S. J. 1965Melanocyte populations in UV-irradiated human skin. , 45 295 8
Raimondi S. Sera F. Gandini S. Iodice S. Caini S. Maisonneuve P. Fargnoli M. C. 2008MC1R variants, melanoma and red hair color phenotype: a meta-analysis. , 122 2753 60
Randerson-Moor J. A. Harland M. Williams S. Cuthbert-Heavens D. Sheridan E. Aveyard J. Sibley K. Whitaker L. Knowles M. Bishop J. N. Bishop D. T. 2001A germline deletion of 14ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. , 10, 1, 55-62.
Reichrach J. Rech M. Moeini M. Meese E. Tilgen W. Seifert M. 2007In vitro comparison of the vitamin D endocrine system in 1,25(OH)2D3-responsive and-resistant melanoma cells. , 6 48 55
Rivers J. K. 2004Is there more than one road to melanoma? , 363 9410 728 30
Rizos H. Puig S. Badenas C. Malvehy J. Darmanian A. P. Jiménez L. Milà M. Kefford R. F. 2001A melanoma-associated germline mutation in exon 1beta inactivates 14ARF, 20, 39, 5543-7.
Rosdahl I. K. 1978Melanocyte mitosis in UVB-irradiated mouse skin. , 58 217 21
Rosengren Pielberg. G. Golovko A. Sundström E. Curik I. Lennartsson J. Seltenhammer M. H. Druml T. Binns M. Fitzsimmons C. Lindgren G. Sandberg K. Baumung R. Vetterlein M. Strömberg S. Grabherr M. Wade C. Lindblad-Toh K. Pontén F. Heldin C. H. Sölkner J. Andersson L. 2008A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. , 40 8 1004 9
Runger T. Kappes U. 2008Mechanisms of mutation formation with long-wave ultraviolet radiation (UVA). , 24 2 10
Rünger T. M. 2011Is UV-induced mutation formation in melanocytes different from other skin cells? , 24 1 10 12
Saxowskya T. Meadowsa K. Klunglandb A. Doetscha W. 2008Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells. , 105 18877 18882
Scherer D. Rachakonda P. S. Angelini S. Mehnert F. Sucker A. Egberts F. Hauschild A. Hemminki K. Schadendorf D. Kumar R. 2010Association between the germline MC1R variants and somatic BRAF/NRAS mutations in melanoma tumors. , 130 12 2844 8
Schwarz A. Ständer S. Berneburg M. Böhm M. Kulms D. van Steeg H. Grosse-Heitmeyer K. Krutmann J. Schwarz T. 2002Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. , 4 1 26 31
Schwarz A. Maeda A. Stander S. van Steeg H. Schwarz T. 2006IL-18 reduces ultraviolet radiation-induced DNA damage and thereby affects photoimmunosuppression. , 176 5 2896 2901
Seltenhammer M. H. Heere-Ress E. Brandt S. Druml T. Jansen B. Pehamberger H. Niebauer G. W. 2004Comparative histopathology of grey-horse-melanoma and human malignant melanoma. Pigment Cell Res, 17(6), 674-81.
Serre C. Lebleu A. Bergeron L. Plantivaux A. Botto J. M. Dal Farra. C. Domloge N. 2011Microarray profiling of gene expression in human keratinocytes suggests a new protective activity against UV-induced DNA damage for a compound previously known to interact with SCF-KIT signalling pathway. , [Epub ahead of print].
Setlow R. B. Woodhead A. D. Grist E. 1989Animal model for ultraviolet radiation-induced melanoma: platyfish-swordtail hybrid. , 86 22 8922 6
Setlow R. B. 1999Spectral regions contributing to melanoma: a personal view. , 4 1 46 9
Silva Idos. S. Higgins C. D. Abramsky T. Swanwick M. A. Frazer J. Whitaker L. M. Blanshard M. E. Bradshaw J. Apps J. M. Bishop D. T. Newton-Bishop J. A. Swerdlow A. J. 2009Overseas sun exposure, nevus counts, and premature skin aging in young English women: a population-based survey. , 129 1 50 9
Smalley K. S. Sondak V. K. Weber J. S. 2009c-KIT signaling as the driving oncogenic event in sub-groups of melanomas. 24 5 643 50Review.
Smoller B. R. 2006Histologic criteria for diagnosing primary cutaneous malignant melanoma. 19, Suppl 2, S 34 40
Song X. Mosby N. Yang J. Xu A. Abdel-Malek Z. Kadekaro A. L. 2009MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytes. , 22 6 809 18
Spatz A. Giglia-Mari G. Benhamou S. Sarasin A. 2001Association between DNA repair-deficiency and high level of 53mutations in melanoma of Xeroderma pigmentosum. 61, 6, 2480-6.
Staricco R. J. Pinkus H. 1957Quantitative and qualitative data on the pigment cells of adult human epidermis. , 28 33 45
Stierner U. Rosdahl I. Augustsson A. Kagedal B. 1989UVB irradiation induces melanocyte increase in both exposed and shielded human skin. , 92 561 564
Sturm R. A. Duffy D. L. Box N. F. Newton R. A. Shepherd A. G. Chen W. Marks L. H. Leonard J. H. Martin N. G. 2003Genetic association and cellular function of MC1R variant alleles in human pigmentation. , 994 348 58
Sturm R. A. Duffy D. L. Zhao Z. Z. Leite F. P. Stark M. S. Hayward N. K. Martin N. G. Montgomery G. W. 2008A single SNP in an evolutionary conserved region within intron 86 of the HERC2 gene determines human blue-brown eye color. Am J Hum Genet, 82(2), 424-31.
Tadokoro T. Kobayashi N. Zmuzka B. Z. Ito S. Wakamatsu K. Yamaguchi Y. Korossy K. S. Miller S. A. Beer J. Z. Hearing V. J. 2003UV-induced DNA damage and melanin content in human skin differing in racial/ethnic origin. , 17 1177 9
Tadokoro A. T. Yamaguchi Y. Batzer J. Coelho S. G. Zmudzak B. Z. Miller S. A. Wolber R. Beer J. Z. Hearing V. J. 2005Mechanisms of skin tanning in different racial/ethnic groups in response to ultraviolet radiation. , 124 1326 32
Takeuchi S. Zhang W. Wakamatsu K. Ito S. Hearing V. J. Kraemer K. H. Brash D. E. 2004Melanin acts as a potent UVB photosensitizer to cause an atypical mode of cell death in murine skin. , 101 42 15076 81
Thomas N. E. Edmiston S. N. Alexander A. Millikan R. C. Groben Hao P. A. H. Tolbert D. Berwick M. Busam K. Begg C. B. Mattingly D. Ollila D. W. Tse C. K. Hummer A. Lee-Taylor J. Conway K. 2007Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. , 16 991 7
Thomas N. E. Kricker A. From L. Busam K. Millikan R. C. Ritchey M. E. Armstrong B. K. Lee-Taylor J. Marrett L. D. Anton-Culver H. Zanetti R. Rosso S. Gallagher R. P. Dwyer T. Goumas C. Kanetsky P. A. Begg C. B. Orlow I. Wilcox H. Paine S. Berwick M. 2001Associations of cumulative sun exposure and phenotypic characteristics with histologic solar elastosis. Genes, Environment, and Melanoma Study Group. Cancer Epidemiol Biomarkers Prev, 19 11 2932 41
Thomas N. Berwick M. Cordeiro M. 2006Could mutations in melanocytic lesions arise from DNA damage induced by ultraviolet radiation. J Invest Dermatol, 126 1693 1696
van Schanke A. Jongsma M. J. Bisschop R. van Venrooij G. M. Rebel H. de Gruijl F. R. 2005Single UVB overexposure stimulates melanocyte proliferation in murine skin, in contrast to fractionated or UVA-1 exposure. , 124 241 7
van Schanke A. van Venrooij G. M. Jongsma M. J. Banus H. A. Mullenders L. H. van Kranen H. J. de Gruijl F. R. 2006Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures. , 66 5 2608 15
van Steeg H. Kraemer K. H. 1999Xeroderma pigmentosum and the role of UV-induced DNA damage in skin cancer. 5 2 86
Veierod M. B. Adami H. O. Lund E. Armstrong B. K. Weiderpass E. 2011Sun and solarium exposure and melanoma risk: effects of age, pigmentary characteristics, and nevi. , 19 111 20
Wachsmuth R. C. Gaut R. M. Barrett J. H. Saunders C. L. Randerson-Moor J. A. Eldridge A. Martin N. G. Bishop T. D. Newton-Bishop J. A. 2001Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study. , 117 348 52
Walker G. J. Kimlin M. G. Hacker E. Ravishankar S. Muller H. K. Beermann F. Hayward N. K. 2009Murine neonatal melanocytes exhibit a heightened proliferative response to ultraviolet radiation and migrate to the epidermal basal layer. , 129 1 184 9
Wang Y. Digiovanna J. J. Stern J. B. Hornyak T. J. Raffeld M. Khan S. G. Oh K. S. Hollander M. C. Dennis P. A. Kraemer K. H. 2009Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. , 106 15 6279 84
Wang H. T. Choi B. Tang M. S. 2010Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts. , 107 27 12180 5
Weiner L. Han R. Scicchitano B. M. Li J. Hasegawa K. Grossi M. Lee D. Brissette J. L. 2007Dedicated epithelial recipient cells determine pigmentation patterns. 130 5 932 42
Whiteman D. Green A. 1999The pathogenesis of melanoma induced by ultraviolet radiation. , 341 766 7
Whiteman D. C. Whiteman C. A. Green A. C. 2001Childhood sun exposure as a risk factor for melanoma: a systematic review of epidemiologic studies. , 12 69 82
Whiteman D. C. Watt P. Purdue D. M. Hughes M. C. Hayward N. K. Green A. C. 2003Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. , 95 806 12
Wolnicka-Glubisz A. Damsker J. Constant S. Corn S. De Fabo E. Noonan F. 2007Deficient inflammatory response to UV radiation in neonatal mice. , 81 6 1352 61
Wood S. R. Berwick M. Ley R. D. Walter R. B. Setlow R. B. Timmins G. S. 2006UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production. , 103 11 4111 5
Yamaguchi Y. Coelho S. G. Zmudzka B. Z. Takahashi K. Beer J. Z. Hearing V. J. Miller S. A. 2008Cyclobutane pyrimidine dimer formation and 53production in human skin after repeated UV irradiation. , [Epub ahead of print].
Yamazaki F. Okamoto H. Miyauchi-Hashimoto H. Matsumura Y. Itoh T. Tanaka K. Kunisada T. Horio T. 2004XPA gene-deficient, SCF-transgenic mice with epidermal melanin are resistant to UV-induced carcinogenesis. , 123 1 220 8
Yamazaki F. Okamoto H. Matsumura Y. Tanaka K. Kunisada T. Horio T. 2005Development of a new mouse model (xeroderma pigmentosum a-deficient, stem cell factor-transgenic) of ultraviolet B-induced melanoma. , 125 3 521 5
Yang G. Curley D. Bosenberg M. Tsao H. 2007Loss of xeroderma pigmentosum C (Xpc) enhances melanoma photocarcinogenesis in Ink4a-Arf-nudeficient mice. 67 12 5649 5657
Zaidi M. R. Davis S. Noonan F. P. Graff-Cherry C. Hawley T. S. Walker R. L. Feigenbaum L. Fuchs E. Lyakh L. Young H. A. Hornyak T. J. Arnheiter H. Trinchieri G. Meltzer P. S. De Fabo E. C. Merlino G. 2011Interferon-γ links ultraviolet radiation to melanomagenesis in mice. , 469 7331 548 53
Zattra E. Fortina A. B. Bordignon M. Piaserico S. Alaibac M. 2009Immunosuppression and melanocyte proliferation. , 19 2 63 8
Zhu G. Duffy D. L. Eldridge A. Grace M. Mayne C. O’Gorman L. Aitken J. F. Neale M. C. Hayward N. K. Green A. C. Martin N. G. 1999A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs. , 65 483 92
Zhu G. Montgomery G. W. James M. R. Trent J. M. Hayward N. K. Martin N. G. Duffy D. L. 2007A genome-wide scan for naevus count: linkage to CDKN2A and to other chromosome regions. , 15 94 102