BJD

British Journal of Dermatology

SYSTEMATIC REVIEW

Single-nucleotide polymorphisms in pigment genes and nonmelanoma skin cancer predisposition: a systematic review M. Binstock, F. Hafeez, C. Metchnikoff and S.T. Arron Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, U.S.A.

Summary Correspondence Sarah Arron. E-mail: [email protected]

Accepted for publication 20 May 2014

Funding sources This publication was supported by the UCSF Nina Ireland Lung Disease Program and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number KL2 TR000143. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Conflicts of interest None declared.

Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A. The two most common NMSCs are basal cell carcinoma and squamous cell carcinoma. The associations of single-nucleotide polymorphisms (SNPs) in pigmentation pathway genes with NMSC are not well characterized. There is a series of epidemiological studies that have tested these relationships, but there is no recent summary of these findings. To explain overarching trends, we undertook a systematic review of published studies. The summarized data support the concept that specific SNPs in the pigmentation pathway are of importance for the pathogenesis of NMSC. The SNPs with the most promising evidence include MC1R rs1805007(T) (Arg151Cys) and rs1805008(T) (Arg160Trp), and ASIP AH haplotype [rs4911414(T) and rs1015362(G)]. There are a few other SNPs found in TYR, OCA2 and SLC45A2 that may show additional correlation after future research. With additional research there is potential for the translation of future findings to the clinic in the form of SNP screenings, where patients at high risk for NMSC can be identified beyond their phenotype by genotypically screening for predisposing SNPs.

DOI 10.1111/bjd.13283

What’s already known about this topic?

•

Single-nucleotide polymorphisms (SNPs) have potential for use in preventative health by identifying markers that are linked to nonmelanoma skin cancer (NMSC).

What does this study add?

• • •

This is the first systematic review of SNPs in genes of the pigmentation pathway and their relationship to NMSC. We provide a succinct summary of existing data by summarizing the impact of individual SNPs on the risk of NMSC through suspected pigmentary and nonpigmentary mechanisms. Additional pigmentation genes that warrant further investigation are identified.

Nonmelanoma skin cancer (NMSC) is the most common cancer in the U.S.A., accounting for more than 1 million new cases per year.1–3 The two most common types of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which occur in a ratio of 4
5 : 1 in the general population.4 The primary risk factor for NMSC is ultraviolet (UV) radiation exposure, which causes DNA damage within the © 2014 British Association of Dermatologists

keratinocyte.5,6 Melanin is proposed to serve as a filter to protect DNA from UV damage.7,8 Patients with fair skin and a propensity to sunburn are at increased risk for NMSC, mediated by the interaction between the skin and UV.9,10 Epidermal pigmentation is a result of melanin synthesis in melanocytes11 and transfer to surrounding keratinocytes for distribution throughout the epidermis of the skin.12–15 British Journal of Dermatology (2014) 171, pp713–721

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714 Pigment gene polymorphisms and skin cancer, M. Binstock et al.

Pigment formation falls into two categories, constitutive and facultative.16 Constitutive pigmentation reflects the basal level of melanin production without additional environmental stimulus. Facultative pigmentation describes an enhanced level of melanin production due to exogenous or endogenous influences, such as exposure to sunlight or stress. This occurs in mature melanocytes and requires the same melanin-producing machinery involved in constitutive pigmentation. The combination of constitutive pigmentation traits and the skin’s facultative reaction to sunlight defines the clinical skin phenotype (CSP). Constitutive pigmentation is assessed through skin complexion, hair colour, eye colour and the presence of freckles. Facultative pigmentation is quantified through the Fitzpatrick skin type, a six-level scale based on a patient’s self-reported tendency to burn or tan.17 NMSC risk is directly associated with CSP,18,19 where predisposing risk factors include fair complexion, light eyes, red or blond hair, propensity to freckle or burn, and inability to tan.18–24 CSP is highly dependent on the production and distribution of melanin within the epidermis, all of which are determined by the proteins encoded by over 150 genes in the pigmentation pathway.25,26 Comparative genomics, positive selection evolution models and genome-wide/specific allele association studies have been used to identify genes and alleles associated with the pigmentation pathway.27 A genome-wide association study (GWAS) utilizes an unbiased screen of 500 000 or more single-nucleotide polymorphisms (SNPs) to identify associations between SNPs and the outcome. If there is a positive correlation between a SNP and a designated trait, it does not necessarily mean that this SNP is responsible for that trait, but rather could imply that the causal variant is linked and may lie within the locus of interest. Because large populations must be screened in order to gain statistical power, an alternative is to analyse a preselected group of candidate SNPs. Multiple studies have applied locus-specific association studies and found that some SNPs in pigment genes are associated with an increased risk of NMSC, some of which remain significant even after controlling for CSP. This implies that these alleles may predispose to NMSC through cellular pathways separate from pigment production. The high-risk CSP traits may thus function as markers for predisposition to NMSC rather than as mediators of the causal mechanism. If this is the case, further research may show that it is more effective to screen patients genotypically using identified high-risk pigment SNPs rather than depending on CSP traits for NMSC prevention. This is the first systematic review covering epidemiological studies of NMSC risk associated with polymorphisms of genes in the pigmentation pathway. The last review on this topic was performed in 2010.28 We provide a basic overview of pigmentation pathway genetics to illustrate areas that have been thoroughly studied and identify areas that warrant further investigation. We summarize the impact of individual SNPs on the risk of NMSC through suspected pigmentary British Journal of Dermatology (2014) 171, pp713–721

and nonpigmentary mechanisms. SNPs from genes that are correlated to pigmentation only through previous GWAS studies are excluded because there is no research showing their biochemical role in pigmentation. Melanoma review is beyond the scope of this paper and extensive reviews exist.29,30 It is outside the scope of this paper to provide the comprehensive biochemistry of the pigmentation pathway. For more information on pigmentation genetics, a list of known loci is available online (http://www.espcr.org/ micemut/); further information is available.31

Materials and methods Eligibility criteria and search Original articles analysing the association between pigmentation pathway gene polymorphisms and skin cancer risk (BCC, SCC and/or NMSC) were included in this systematic review. The study needed to be published as a full-text article in English. The PubMed and Web of Science databases were searched from their earliest holdings to 16 May 2014 using the Boolean operator “((squamous cell carcinoma) OR (basal cell carcinoma) OR (skin cancer)) AND ((gene polymorphism) OR (genome wide) OR (GWAS) OR (variant)) AND ((pigment) OR (pigmenta*))”. Selection Two authors (M.B. and F.H.) independently assessed all of the titles and abstracts of studies generated by the internet searches. Full-text versions of eligible articles were obtained and their cited references were examined for additional eligible studies. Any disagreement was resolved through discussion via a third party (S.T.A.). Data extraction Two of the authors (M.B. and F.H.) independently extracted the following data for each study: author, study date, study population size (control, SCC, BCC, NMSC groups), number of SNPs tested, relevant pigmentation SNPs, and association between the SNP and SCC, BCC and/or NMSC [odds ratios (ORs), confidence intervals (CIs) and variables controlled during analysis] (Table S1; see Supporting Information). Analytical models in studies were heterogeneous in their measurement of the relationship between the SNP and NMSC, so we noted their model as additive, multiplicative, single heterogeneous genotype, allelic frequency or unknown. We extracted values only with significant findings, noted ‘ns’ if it was not significant, and ‘–’ if the relationship was not tested. Priority was placed on extracting ORs and CIs that were controlled for CSP and/or tested in combined population sets. The extracted data were classified into two groups and sorted by genes: genes associated with constitutive pigmentation and genes associated with facultative pigmentation. © 2014 British Association of Dermatologists

Pigment gene polymorphisms and skin cancer, M. Binstock et al. 715

Results Literature search Figure 1 summarizes the selection process of studies that measured the relationship of pigmentation pathway SNPs to NMSC risk. Our initial search resulted in 518 articles, and 457 after duplicates were removed. From this group, 40 were selected based on title and abstract and after these studies were read in full, 17 were selected to include in our review. We included three additional studies from the references of the 17, resulting in a total of 20 articles in our review. There were three notable studies that were excluded from our systematic review. Two of these were reviews,28,29 and although Gerstenblith et al.29 was a meta-analysis, the article did not present new data on the relationship of pigmentation pathway SNPs to NMSC risk. Ferrucci et al.32 was excluded because the study did not test individual MC1R SNP relationships to NMSC, but rather lumped SNPs together during analysis.

S2; see Supporting Information). Studies ranged in size from single-centre cohorts of a couple of hundred participants to multicentre pooled analyses with over 35 000 patient participants. They also varied in the number of SNPs simultaneously tested, the least number being one and the most being greater than 500 000 SNPs. There were three GWASs and the 17 other studies were locus-specific associated studies that tested a pre-selected group of candidate SNPs. Fourteen studies tested their associations in a single population, while the other six either replicated their findings in additional populations or pooled multiple populations in a meta-analysis fashion. In general, the correlations between SNPs and NMSC found in larger populations are more robust, with GWASs being the most reliable due to the combination of testing many SNPs in large populations. Of added interest to our study is when significant correlations between SNPs and NMSC risk are retained after controlling for CSP traits during analysis. Results from all included studies are given in Table S1 (see Supporting Information).

Description of the included studies

Discussion

In total, 20 studies were selected for our systematic review and were published between the years 1998 to 2013 (Table

This study was designed to review the genes known to play a biochemical role in the pigmentation pathway. Some SNPs

Web of Science n = 257

PubMed n = 261

Articles retrieved by search strategy (n = 457)

Exclude duplicates (n = 61)

Articles selected based on title and abstract (n = 40) Main reasons for exclusion (n = 23) • Described molecular biology and not relationship to cancer (n = 4) • Did not relate to pigment (n = 2) • No analysis of relationship or susceptibility to NMSC (n = 4) • Did not test individual SNPs (n = 1) • Abstracts at conference (n = 4) • Only described methods (n = 2) • Review (n = 6)

Articles selected based on full text (n = 17)

Fig 1. Flowchart of the literature selection process. Results of search strategy and reasons for exclusion. NMSC, nonmelanoma skin cancer; SNP, single-nucleotide polymorphism. © 2014 British Association of Dermatologists

Reference list n=3 Included articles n = 20

British Journal of Dermatology (2014) 171, pp713–721

716 Pigment gene polymorphisms and skin cancer, M. Binstock et al.

Supporting Information).36–38 Melanoblasts have a receptor for KIT ligand (KITLG) and this cascade is key to the survival and migration of the melanoblast (Fig. 2a).39 As KITLG has no associated pigmentary disorders, it may be of interest to test the KIT receptor gene instead, as it is known to cause the hypo-pigmentary disorder of piebaldism. Other genes that may be of interest to test include PAX3, SOX10, MITF, EDN3 and EDNRB as they play key roles in melanocyte differentiation. This is characterized by the pigmentary abnormalities that result when mutations in each cause specific types of Waardenburg syndrome. More information on key melanocyte differentiation genes and their associated disorders may be found in recent reviews.40,41

not included in this systematic review have been associated with NMSC through GWAS, but have no known functional role in the pigmentation pathway. These genes include IRF4, EXOC2, UBAC233,34 and the recently reported TGM3 and RGS22.35 An approach to reason through the relationships between the included pigmentation SNPs and risk of NMSC is to question what aspect of melanin production is altered that either increases or decreases the susceptibility of developing NMSC. Because melanin is proposed to be a key mediator in protection from skin cancer,7,8 we organized these SNPs by the gene that they belong to and where that gene’s function lies in the pathway of melanin synthesis. It cannot be assumed that the SNP is what causes the functional difference of the gene, as it may be linked only to the genetic region responsible for this measured statistical relationship. As genetic variation within the pigmentation pathway often results in visible phenotypic differences, it is peculiar when the statistically significant relationship is retained after controlling for the SNP–NMSC interaction for CSP. It forces us to consider other roles outside of the pigmentation pathway that the gene may serve.

Melanosome biogenesis: premelanosome: stages I and II Melanosome development within mature melanocytes is divided into a four-stage process of protein trafficking and assembly. Stage I corresponds to the domains of early endosomes whose membrane is enriched with premelanosome protein 17 (PMEL17),42 the main protein component of fibril sheets in melanosomes.43 PMEL17 polymerizes and emanates from the intraluminal vesicles forming a parallel pattern,44 a critical step in the development of stage II melanosomes.45 The melanosome-membrane-associated G-proteincoupled receptor 14346,47 and melanoma antigen recognized by T cells 1 have been shown to localize specifically to premelanosomes through proteomic analysis.45 None of these genes has been analysed in relationship to NMSC, but they are key candidates for testing due to their importance in premelanosome structural formation and composition.

Constitutive pigmentation Melanocyte differentiation The first step of pigment formation begins during embryogenesis where melanoblasts originate, migrate and differentiate to melanocytes. Although many proteins play an active role in this step, only one SNP from KITLG has been tested for its relation to BCC, with insignificant findings (Table S1; see

UV

(a) p53

Keratinocyte

(b)

Tyrosine TYR

α-MSH

POMC

Dopaquinone (DQ) Cysteine α-MSH

Cyclodopa ASIP

M

C1

IV.

R

III. MA TP

II.

TY

R

KIT

CREB P

MITF MITF Genes coding: melanoblast (development, migration, response, melanosome biogenesis, melanogenesis, dendricity, apoptosis

5 4A

cAMP cascade

Dopachrome T DC

tein SLC P-Pro 2

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RP

TY

DHI

DHICA TYR TYR P1

Eumelanin

Reduction

ATR N KITLG

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Fig 2. Pigmentation pathway and melanogenesis. (a) Map of the pigmentation pathway. Genes that have colour-coded proteins have been tested. Proteins that do not have a colour have not been tested; some are included to explain better the pathway depicted. Red is melanocyte differentiation, dark blue is mature melanosome development and green is facultative pigmentation. (b) Melanogenesis biochemistry. ASIP, agouti signalling protein; ATRN, attractin; CREB, cAMP response element binding protein; DHI, dihydroindole; DHICA, DHI carboxylic acid; MATP, macrodomain Ter protein; MC1R, melanocortin 1 receptor; MITF, microphthalmia-associated transcription factor; MSH, melanocyte-stimulating hormone; SLC, solute carrier; TYR, tyrosinase; TYRP, TYR-related protein; UV, ultraviolet. British Journal of Dermatology (2014) 171, pp713–721

© 2014 British Association of Dermatologists

Pigment gene polymorphisms and skin cancer, M. Binstock et al. 717

Melanosome biogenesis: mature melanosome: stages III and IV In the transition from stage II to stage III large quantities of eumelanin are produced and deposited on the fibrillar sheets, making them appear thicker and darker; by stage IV they are completely masked (Fig. 2a). PMEL17 has been shown to increase the rate of melanin polymerization in vitro.44 The key melanogenesis enzymes, tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1) and dopachrome tautomerase (DCT) (or tyrosinase-related protein 2), are enriched in the melanosome membrane48 during the stage II to III transition.42,49 TYR is copper dependent and controls the rate-limiting step of melanogenesis by oxidizing L-tyrosine to dopaquinone (DQ), the melanin precursor (Fig. 2b). TYR, TYRP1 and DCT catalyse specific reactions to form eumelanin. In pheomelanin synthesis, DQ undergoes addition of cysteine followed by redox reactions to form pheomelanin.50,51 When melanosomes predominantly produce pheomelanin they resemble premelanosomes, with a round and nonfibrillar structure, containing splotchy and irregular deposits of melanin.45,52 Melanosomal pH may regulate melanogenesis.53 Melanosomelocalized ion channels include P-protein (coded by OCA2), which is thought to regulate pH through counter anion transport,49,54 the sodium–calcium exchanger solute carrier family 24 member 5 (SLC24A5),55 and solute carrier family 45 member 2 (SLC45A2) (or MATP).56 There are numerous hypopigmentary diseases caused by dysfunctions of the melanogenesis proteins above. Oculocutaneous albinism (OCA) 1, 2, 3 and 4 stem from direct mutations in the coding regions of TYR, OCA2, TYRP1 and SLC45A2, respectively. Patients with OCA are at an increased risk of NMSC. SNPs in these OCA1–4 genes and SLC24A5 have been tested in locusspecific association studies for NMSC risk in the general population (Table S1; see Supporting Information). For TYR, one study found that Ser192Tyr was associated with an increased risk of SCC while controlling for CSPs and familial history of skin cancer.25 This relationship lost significance after Bonferroni correction and has not been tested by any other studies. Arg402Gln in TYR was found to increase risk of BCC in a pooled population study,36 but this relationship was not significant when tested by three other studies.25,37,57 In OCA2, seven SNPs in total have been tested by five separate studies,25,34,36,37,58 but rs1800407 (Arg419Gln) is of most interest due to testing by multiple studies. Nan et al.25 found that Arg419Gln was associated with an increased risk of BCC while controlling for CSPs and familial history of skin cancer. This relationship lost significance after Bonferroni correction and duplication by Kosiniak-Kamysz et al.37 was insignificant. This same SNP was found to be associated with increased risk of NMSC in a third study that pooled multiple populations during analysis,58 supporting the finding of Nan et al.25 The findings that both rs1042602 (Ser192Tyr) of TYR and rs1800407 (Arg419Gln) of OCA2 were nominally significant when controlled for CSP implies that these genes may predispose to NMSC through pathways outside of melanin synthesis. It has © 2014 British Association of Dermatologists

been demonstrated that TYR is recognized as a melanoma-associated antigen by cytotoxic T lymphocytes59 and that the protein product of OCA2 increases cellular sensitivity to toxic compounds.60 It would be interesting to test these SNPs further in larger datasets to see whether the risk associations are supported. The findings from tests of SLC45A2, TYRP1 and SLC24A5 were minimal (Table S1; see Supporting Information). Four SNPs in SLC45A2 were tested by five studies.25,34,37,58,61 One study that pooled multiple populations found that rs16891982 (G) had an increased risk for both BCC and SCC,61 but three other studies did not significantly correlate this SNP with NMSC risk.25,37,58 In TYRP1 five studies tested rs1408799 (C>T) and found no significant relationships with SCC, BCC or NMSC.25,36,37,57,58 In SLC24A5 two studies tested rs17426596 (T>C) and found no significant relationships with SCC, BCC or NMSC.25,58 Because many of the tests resulted in repeated negative findings for the above SNPs, it seems reasonable that they do not predispose to NMSC. It could be argued that more tests should be performed in additional populations as ethnic or geographic backgrounds of participants may vary and influence whether or not two studies agree. One gene that has not been studied, but does play a key role in melanin synthesis, is DCT. Additionally, it is of interest to test the genes responsible for the various Hermansky–Pudlak syndromes, as each result in altered CSP and increased skin cancer risk. These genes code for proteins that localize mature melanosomal enzymes and transporters; readers are directed to a detailed review for additional information.62 Melanosome transport The final stage of the melanosome occurs when it is transferred to the keratinocytes. Although there is a series of motor proteins, linking complexes and membrane proteins that facilitate this movement and transfer, no coding genes have been tested for their relationship with NMSC.63,64 There is a family of single-gene disorders known as Griscelli syndrome types I–III characterized by pigment dilution in the hair and skin,65,66 but they have not been shown to be linked to NMSC risk, so they would most likely not be candidates for future study. Facultative pigmentation Tanning is characterized by an increased production of eumelanin in response to UV radiation67 and is controlled by the melanocyte membrane-localized G-protein-coupled melanocortin-1 receptor (MC1R). Alpha-melanocyte-stimulating hormone (a-MSH), a cleavage product of proopiomelanocortin (POMC), is an agonist to MC1R; agouti signalling protein (ASIP) is an antagonist. UV exposure leads to an increased expression of a-MSH and initiation of MC1R signal transduction.68 When activated, MC1R stimulates MITF, which transcribes key melanogenesis proteins for eumelanin synthesis (Fig. 2a).69 Variants in MC1R are associated with red hair colour (RHC).27 Functional analysis of these RHC SNPs reveal British Journal of Dermatology (2014) 171, pp713–721

718 Pigment gene polymorphisms and skin cancer, M. Binstock et al.

decreased abilities of the linked alleles to activate signal transduction, thus decreasing synthesis of eumelanin-producing machinery, favouring pheomelanin synthesis.70 There have been two GWASs33,38 and multiple locus-specific studies32,34,36,37,57,71–79 testing the association between MC1R variants and NMSC (Table S1; see Supporting Information). One or more copies of any MC1R variant increases the risk of NMSC,32,36,73–78 and having one or more RHC-specific variant further increases this risk.32,36,37,57,74,77,78 Some studies adjusted for CSP including Fitzpatrick type and eye and hair colour and found an independent relationship between the SNPs and NMSC;33,72,77 including MC1R variant status to host factors of age, sex and CSP have had modest additive results in NMSC risk prediction models.75,77 Given the scarcity of studies in this area, this extra contribution has not been fully quantified and it is uncertain whether it is large enough to be clinically useful. Other genes related to MC1R signal transduction have been tested in their relationship to NMSC, including POMC, ASIP and attractin (ATRN), a low-affinity ASIP receptor that influences mouse coat colour.80,81 Neither POMC nor ATRN were found to have a significant association with NMSC,25,58 but various SNPs from ASIP have been tested, with significant findings (Table S1; see Supporting Information).25,36,58,79,82 As all of these SNPs were tested in the same studies and only ASIP showed significance, it may be that ATRN does not play as important a role in melanin production as does ASIP. It may also be that POMC is more highly conserved due to critical functions of the protein and therefore may possibly have fewer SNPs that can lead to increased susceptibility to NMSC. Many of the significant findings in MC1R and ASIP showed an increased risk of NMSC independent of CSP, suggesting that there may be other mechanisms beyond pigmentation relating these variants to the susceptibility of NMSC. a-MSH and other POMC peptides also have immunomodulatory and anti-inflammatory activity.83–85 As UV radiation induces the release of aMSH in the epidermis,86,87 a-MSH may regulate inflammatory stimuli and contribute to UV-mediated immunosuppression.88 a-MSH and other POMC peptides affect proliferation and differentiation of both melanocytes89–92 and keratinocytes,93 indicating that these proteins are potential mediators of hyperproliferative skin diseases.94 It has also been suggested that the immune and inflammatory responses to UV exposure are mediated via the MC1R gene.95–98 Additionally, pheomelanin may contribute to skin carcinogenesis by producing free radicals in response to UV radiation.73

Conclusion We show that some single-nucleotide variants in genes of the pigmentation pathway are associated with NMSC, and may play a role in risk-prediction modelling. Whether CSP is causal or a biomarker of NMSC risk is still unclear. Many SNPs, particularly in MC1R, are associated with NMSC risk independent of CSP, suggesting that they may predispose to NMSC through a biochemical pathway outside of or beyond pigment producBritish Journal of Dermatology (2014) 171, pp713–721

tion. These studies suggest that there is value in using pigmentation pathway genotypic information to predict NMSC risk, but more testing must be performed with larger cohorts to see whether these inferences are reliable and significantly additive to CSP. Further study of the biochemical properties of allelic variants in pigmentation genes and other genes associated with NMSC will shed light on how these specific variants exert their effects on CSP and NMSC risk, providing a better understanding of the complex molecular pathogenesis of NMSC.70

Acknowledgments The authors thank M.M. Chren and E. Linos for critical reading of this manuscript.

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Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s website: Table S1 Summary of study-specific findings. Table S2 Summary of studies included in this systematic review.

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