Abstract and Introduction
Abstract
Genetic predisposition to melanoma and nonmelanoma skin cancer extends far beyond the Fitzpatrick phenotype classification scheme. Specific alleles of the gene that codes for the malnocortin 1 receptor are predictive of skin cancer risk independent of skin type and hair color. The ability to identify high risk patients independent of the red hair phenotype may help to modify routine sun and skin monitoring behaviors. In addition, as this increased skin cancer risk is likely due to impaired UVA and UVB defence mechanisms, consideration of genetic predisposition may also be appropriate for patients undergoing psoralen + UVA (PUVA) or UVB treatments for various cutaneous disorders, such as psoriasis, eczema, and vitiligo. Testing aimed at improving prognostication may serve to limit the influence of certain risk factors.
Introduction
It has long been known that cutaneous pigmentation is our principal photoprotective defence against the carcinogenic and aging effects of ultraviolet radiation (UVR). Recent evidence,1 however, indicates that much of the defence provided by eumelanin is independent of pigmentation. This photoprotective mechanism, therefore, is determined not only by the quantity of eumelanin in the skin, but also by the variants of eumelanin.
Melanocortin 1 Receptor (MC1R)
The melanocortin 1 receptor (MC1R or alpha melanocytestimulating hormone receptor) is a key protein regulating skin and hair pigmentation. Melanin synthesis is largely modulated by the agonistic binding of alpha-melanocortin (alpha-MSH) and adrenocorticotropic hormone (ACTH) to MC1R. This initiates the cAMP mediated pathway required for UV-induced tanning and ultimately yields the blackbrown pigment (eumelanin). Total melanin content (quantity and variety), as well as the relative amounts of eumelanin and phaeomelanin, are important determinants for skin color, hair color and photoprotection.
Melanin-containing granules (melanosomes) form supranuclear caps in keratinocytes, thus shielding the nuclear deoxyribonucleic acid (DNA) from UVR. In dark skin, melanosomes are found throughout the epidermis, but in fair skin they are absent from the suprabasal layer, allowing for increased UVR penetration and DNA damage.[2,3] Eumelanin is also a scavenger for reactive oxygen species (ROS).[3] On the other hand, phaeomelanin may contribute to UV-induced skin damage due to its potential to generate singlet oxygen and hydroxyl radicals in response to UVR.[3,4] Furthermore, it is also known that the chromophore backbone of eumelanin is responsible for the absorption and scattering of UVR; however, there are several different chromophore monomer units and not all perform this function equally well. As such, it is clear that eumelanin does much more than pigment our skin and there are potential clinical outcomes associated with the eumelanin mix that we are genetically coded to produce.
More than 120 genes have been shown to regulate pigmentation,[5] with a key gene being HomoloGene 1789 (locus: Chr.16:q24.3). This gene encodes the MC1R, a 7-transmembrane G protein-coupled receptor (GCR) expressed on the surface of melanocytes. The modulation of MC1R function regulates melanin synthesis both qualitatively and quantitatively.[6] The human MC1R gene is highly polymorphic with over 70 identified alleles.[7] Certain allelic variants are associated with the red hair phenotype (red hair, fair skin, lack of tanning ability, and propensity to freckle),[5] melanoma, and nonmelanoma skin cancer.[2,8–11] The MC1R gene is, of course, not the only gene that is associated with skin cancer risk, but it has been widely studied. As well, 7 identified risk alleles,[5,9–11] independent of skin type and hair color, appear to confer a greater risk of nonmelanoma skin cancer, melanoma, and photoaging.
Exposing cultured human melanocytes to increasing doses of UVR has shown that total melanin and eumelanin content (MC and EC) correlate inversely with the extent of UVR-induced growth arrest, apoptosis, and induction of cyclobutane pyrimidine dimers (CPD). Melanocytes with loss-of-function MC1R, regardless of their MC or EC, sustained more UVR-induced apoptosis and CPD, and exhibited reduced CPD repair. MC, mainly EC, and MC1R function are therefore independent determinants of UVR-induced DNA damage in melanocytes.[3] This may help to explain why the predictive value for skin cancer and photoaging from alleles that code for the MC1R receptor are independent of skin type and hair color.
Furthermore, in helping to explain the independence of photoprotection and pigmentation, it has been demonstrated that melanocortins reduce the generation of hydrogen peroxide and enhance repair of DNA photoproducts independently of pigmentation. Natural expression of certain MC1R allelic variants sensitizes melanocytes to the cytotoxic effect of UVR and increases the burden of DNA damage and oxidative stress.[1]
It is clear, therefore, that the Fitzpatrick classification of skin type and hair color is insufficient to predict susceptibility to the photo consequences of UVR. While there is no doubt that Fitzpatrick skin type I is more susceptible to burning, skin cancer, and photoaging, the large number of melanoma and nonmelanoma skin cancer patients seen in clinical practice presenting with Fitzpatrick skin types II, III, and IV suggest that additional diagnostic tools are required to identify the spectrum of at-risk patients.
Early work performed in the UK identified a dosage effect of MC1R alleles on sensitivity to UVR (degree of tanning after repeated sun exposure).[12] Given that red hair approximates an autosomal recessive trait and that there is a higher risk for sun sensitivity amongst heterozygotes of certain allelic variants of the MC1R, this gene is likely associated with diversification in the skin's response to UVR in a majority of the population without red hair. As heterozygotes for the MC1R gene are common, this suggests that the MC1R gene may be regarded with substantial importance as a susceptibility gene for sunburn, photoaging, and skin cancer.[12]
Studies of MC1R Associated Skin Cancer Risk
In 2000, an Australian investigation across 859 subjects showed MC1R variants in 72% of individuals with cutaneous malignant melanoma (CMM), whereas only 56% of the control individuals carried at least 1 variant (P<>[13] doubled the risk for CMM for each additional allele carried (odds ratio [OR]=2.0; 95% confidence interval [CI] 1.6–2.6).[8]
In 2001, a broader Dutch study across 961 subjects showed that numerous MC1R gene variants predisposed individuals to cutaneous melanoma. In stratified analyses, the genetic predisposition was shown to be largely independent of skin type and hair color. The ORs, after adjusting for skin type, were 3.6 (95% CI 1.7–7.2) for 2 variants and 2.7 (95% CI 1.5–5.1) for 1 variant. The Asp84Glu variant appeared to confer the highest risk.[9]
As the tendency to sunburn and inability to tan after sun exposure are known risk factors for both melanoma and nonmelanoma skin cancer,[14–18] the interest to further investigate the MC1R gene as a predictive indicator for nonmelanoma skin cancer was pursued.
A second Australian study investigated 220 individuals [111 high risk and 109 low risk for basal cell (BCC) and squamous cell carcinomas (SCC)]. Comparative allele frequencies for 9 MC1R variants were determined. An association was demonstrated between the prevalence of BCC, SCC, and solar keratosis (OR=3.15; 95% CI 1.7–5.82) and 3 alleles with a known association with skin UV sensitivity and melanoma. It was concluded that the presence of at least 1 variant allele was informative in predicting risk beyond that gained from observation of pigmentation phenotype.[10]
A larger study involving 838 subjects (453 with nonmelanoma skin cancer and 385 with no skin cancer) found that the presence of 2 variant alleles indicated increased risk of developing cutaneous SCC (OR=3.77; 95% CI 2.11–6.78), nodular BCC (OR=2.26; 95% CI 1.45–3.52), and superficial multifocal BCC (OR=3.43; 95% CI 1.92–6.15) when compared with carriers of 2 wild type alleles. Furthermore, when stratified by skin type and hair color, the analysis demonstrated that these factors did not materially alter the relative risks.[11]
It is important to note that all observed odds ratios are expressed as multiples of some baseline level of risk; in this report, it is defined as the level or risk seen with that of none of the studied MC1R risk alleles being present.
Epidemiology
With respect to melanoma, public awareness is increasing, but its incidence is rising at an annual rate of 4–5%. The melanoma incidence in Australia is the highest in the world, exceeding 50 per 100,000 individuals. The lifetime risk of developing melanoma in the US is 1 out of 52 in men and 1 out of 77 in women.19 In the US in 2005, 59,000 people were diagnosed with melanoma and 7700 died of the disease, which translates to about 1 melanoma death per hour.
Melanoma represents one of the most common types of cancer occurring in young adults; it is the leading cause of skin cancer death among this population. Recent data from Cancer Research United Kingdom has shown that skin malignancies have overtaken cervical cancer as the most prevalent cancer striking British women in their 20s.[20] Although women in this age group represent only a small percentage of patients diagnosed with melanoma, nearly one-third of all cases occur in those younger than 50 years.[20]
In the US, there has been a 15-fold increase in the incidence of melanoma over the last 40 years, which is a more rapid rate of growth than any other malignancy.[21] As early metastasis is possible and late stage disease usually fatal, prevention and early detection are crucial. The potential cost savings to the health care system resulting from implementation of these measures in both melanoma and nonmelanoma skin cancer can be significant. It is well known that adopting sun awareness, safer "in sun" behaviors, and greater vigilance, as well as diagnostic advances, can save lives and reduce health care costs. Consequently, screening for specific MC1R allelic variants that could identify patients at higher risk for skin cancer and photoaging independent of their skin type or hair color has generated great interest.
Genomic Testing of MC1R
It is now possible to accurately assess the MC1R receptor using a noninvasive skin sample taken with an epithelial swab. A commercial test is presently available in Canada (and soon in other countries) that identifies the 7 high-risk genetic markers associated with MC1R for melanoma, nonmelanoma skin cancer, and photoaging that are independent of skin type and hair color. The gene assays are performed by a central laboratory and results are generally return to the doctor's office in 14 days.
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