In this issue, Hacker and colleagues provide further evidence that molecular subtypes of malignant melanoma may develop along divergent pathways. The authors did not find an association between somatic BRAF-mutant melanoma and germline melanocortin-1 receptor (MC1R) gene status. We discuss this seeming paradox in light of previous studies demonstrating strong associations

Begg, C.B.

Berwick, M.

Conway, K.

Kanetsky, P.A.

Thomas, N.E.

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Melanoma Molecular Subtypes: Unifying and Paradoxical ResultsNancy E. Thomas1, Peter A. Kanetsky3, Colin B. Begg4, Kathleen Conway2, and MarianneBerwick51 Department of Dermatology, Lineberger Comprehensive Cancer Center, University of NorthCarolina, Chapel Hill, NC2 Department of Epidemiology, Lineberger Comprehensive Cancer Center, University of NorthCarolina, Chapel Hill, NC3 Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine,Philadelphia, PA4 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, NewYork, NY5 Department of Medicine, Division of Epidemiology, University of New Mexico, Albuquerque, NMAbstractHacker et al. (in this issue) provide further evidence that molecular subtypes of malignant melanomamay develop along divergent pathways. Hacker et al. did not find an association between somaticBRAF-mutant melanoma and germline melanocortin-1 receptor (MC1R) gene status. We discuss thisseeming paradox in light of previous studies showing strong associations.Keywordsepidemiology; dermatology; etiology; skin pigmentation; oncogene; BRAF; MC1R; melanocortin-1receptor; melanin; mole; nevusIntroductionHacker et al. (2009) contribute new data indicating how BRAF-mutant melanomas can beincluded (2009) in their previously proposed divergent pathway model for melanomadevelopment. Their findings lend support to BRAF-mutant melanomas developing along apathway positively associated with young age at diagnosis, high nevus counts, contiguousnevus remnants, and ability to tan and inversely associated with evidence of high level oflifetime cumulative sun exposure. However, Hacker et al. found no association betweengermline melanocortin-1 receptor (MC1R) status and BRAF-mutant melanomas in anAustralian population-based study. These results differ from two earlier publications (Fargnoliet al., 2008; Landi et al., 2006) that reported strong associations in three independentpopulations (two from Italy and one from San Francisco).Correspondence to: Nancy E. Thomas, MD, PhD, Department of Dermatology, University of North Carolina, 3100 Thurston BowlesBldg., CB#7287, Chapel Hill, NC 27599. Phone: (919) 966-0785; Fax: (919) 966-6460; nthomas@med.unc.edu.CONFLICT OF INTERESTThe authors state no conflict of interest.NIH Public AccessAuthor ManuscriptJ Invest Dermatol. Author manuscript; available in PMC 2011 January 1.Published in final edited form as:J Invest Dermatol. 2010 January ; 130(1): 12–14. doi:10.1038/jid.2009.332.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptDivergent pathwaysThe results of Hacker et al. are concordant with many other studies which have found distinctrisk factors for melanomas harboring BRAF mutations. Both hospital and population-basedstudies on different continents have found BRAF mutations to be associated with young age atdiagnosis (Edlundh-Rose et al., 2006; Liu et al., 2007; Thomas et al., 2007). Others havereported that BRAF-melanomas were associated with contiguous nevus remnants on histologicsections (Edlundh-Rose et al., 2006; Poynter et al., 2006). Similar to Hacker et al., BRAF-mutant melanomas have been reported to be associated with high back nevus counts andincreased ability to tan in a North Carolina population-based study (Thomas et al., 2007). Otherstudies have found BRAF-mutant melanomas to be inversely associated with chronicallyexposed anatomic site and solar elastosis, providing further evidence of an inverse associationwith high levels of cumulative sun exposure (Curtin et al., 2005)Paradox and possible explanationsHacker et al. (2009) report no association between germline MC1R variants and BRAF-mutantmelanomas in 123 cases from Australia. Similarly, we examined the relationship betweenMC1R status and BRAF-mutant melanomas in our North Carolina population-based study; and,similar to that of Hacker et al., our results do not support a strong association.1 In contrast,Landi et al. scored independent sets of 86 and 112 melanoma specimens from a case-controlstudy in Italy and a hospital-based series in San Francisco for histologic evidence of chronicsun damage (CSD). The majority, 56 and 58, respectively, did not show CSD. They reportedthat MC1R variants were strongly associated with BRAF-mutant melanomas in biopsies withlittle histologic evidence of chronic sun damage (non-CSD) (Landi et al., 2006). More recently,in a separate case-control study in Italy including 92 melanomas typed for BRAF mutations,Fargnoli et al. also found germline MC1R variants to be strongly associated with BRAF-mutations, independent of CSD status (Fargnoli et al., 2008).There are several possible explanations for the differing results among these studies. First,dissimilar estimates may be due, in part, to unique effects of specific MC1R variants, thefrequencies of which differ somewhat among study populations. Secondly, there may beunidentified genotypic variation among populations that affects the association of MC1Rvariants with BRAF-mutant melanoma. For example, inherited variants in other genes relatedto pigmentation, tanning response, or nevus propensity might influence this association.Furthermore, environmental differences, in particular ambient sun exposure, could affect therelationship.Gene-environment interactions involving MC1R could be quite complex because MC1Rfunctional status alone might have opposing effects on risk of BRAF-mutant melanoma, asshown in Figure 1. In this model, we assume that basal pheomelanin production is the nullphenotype of MC1R and that epidermal pheomelanin levels do not vary between the groupsbased on findings that MC1R mutations reduce eumelanin but do not change pheomelaninconcentration in mouse tail epidermis (Van Raamsdonk et al., 2009). Inheritance of decreasedfunction MC1R variants might increase the risk of BRAF-mutant melanoma through diminishedconstitutive and facultative pigmentation, less effective DNA damage response mechanisms,and increased generation of hydrogen peroxide (Abdel-Malek et al., 2008). However, carriageof more functional MC1R variants might increase risk because eumelanin, as well aspheomelanin, can contribute to oxidative stress (Meyskens et al., 2004), and individuals withmore eumelanin may increase their sun exposure due to their relatively decreased sunsensitivity.1SubmittedThomas et al. Page 2J Invest Dermatol. Author manuscript; available in PMC 2011 January 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptDue to these competing effects, it is possible that genotypes with an intermediate loss ofMC1R function might produce a favorable host phenotype for production of BRAF-mutant neviand melanoma. A combination of some eumelanin and decreased DNA damage responses maybe most conducive to increased risk of BRAF mutations. Concordant with this possibility isthe finding that individuals with more than one MC1R red hair variants (“R/R”) as defined byDuffy et al. tend to have fewer nevi (Duffy et al., 2004), which frequently harbor BRAFmutations. In addition, patients with albinism, who have melanocytes but who do not produceeumelanin, are at low risk of developing melanoma (Ihn et al., 1993). Furthermore, MC1Renhances repair of DNA photoproducts independent of pigmentation (Abdel-Malek et al.,2008), and MC1R variants increase the risk of melanoma even in individuals with darkercomplexions, a characteristic which normally would be considered protective (Kennedy etal., 2001; Palmer et al., 2000).Because all studies to date examining the association of MC1R variants with BRAF-mutantmelanoma are relatively small, we cannot rule out the possibility that differing results are dueto chance alone, and further investigation with larger populations will clarify the relationship.In addition, few MC1R “R/R” participants have been represented in the studies to date, makingit difficult to assess the odds of BRAF-mutant melanoma in individuals with very loweumelanin levels with simultaneously decreased DNA damage responses due to their MC1Rstatus. Other genes which regulate tanning responses or pigmentation might be expected tohave less influence on eumelanin production in these individuals.Increased statistical power along with ample representation of different populations, includingthose with different European ancestries, should help to solve this problem. This work couldbe approached through larger studies or meta-analyses including diverse populations. Genome-wide association and candidate pathways studies to identify and assess additional inheritedmelanoma risk factors should provide complementary information. Genotypic variants may befound that are associated with BRAF-mutations or modify the relationship between MC1Rvariants and BRAF mutations in melanoma. Candidate pathways of interest include those thataffect pigment phenotype, tanning response, nevus propensity, and DNA damage response.An increased ability to assign inherited differences and somatic alterations in melanoma topathways in the divergent pathway model of melanoma development should help ourunderstanding of melanoma risk and lead to better risk prediction and targeted prevention.AcknowledgmentsThis work was supported by a Lineberger Comprehensive Cancer Center grant, National Cancer Institute grantsCA112243 and CA112524, and a National Institute of Environmental Health Science grant ES014635.AbbreviationsMC1R melanocortin-1 receptorReferencesAbdel-Malek ZA, Knittel J, Kadekaro AL, Swope VB, Starner R. The melanocortin 1 receptor and theUV response of human melanocytes--a shift in paradigm. Photochem Photobiol 2008;84:501–508.[PubMed: 18282187]Beaumont KA, Shekar SN, Cook AL, Duffy DL, Sturm RA. Red hair is the null phenotype of MC1R.Hum Mutat 2008;29:E88–E94. [PubMed: 18484624]Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of geneticalterations in melanoma. N Engl J Med 2005;353:2135–2147. [PubMed: 16291983]Thomas et al. Page 3J Invest Dermatol. Author manuscript; available in PMC 2011 January 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptDuffy DL, Box NF, Chen W, Palmer JS, Montgomery GW, James MR, et al. Interactive effects of MC1Rand OCA2 on melanoma risk phenotypes. Hum Mol Genet 2004;13:447–461. [PubMed: 14709592]Edlundh-Rose E, Egyhazi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, et al. NRAS and BRAFmutations in melanoma tumours in relation to clinical characteristics: a study based on mutationscreening by pyrosequencing. Melanoma Res 2006;16:471–478. [PubMed: 17119447]Fargnoli MC, Pike K, Pfeiffer RM, Tsang S, Rozenblum E, Munroe DJ, et al. MC1R variants increaserisk of melanomas harboring BRAF mutations. J Invest Dermatol 2008;128:2485–2490. [PubMed:18368129]Ihn H, Nakamura K, Abe M, Furue M, Takehara K, Nakagawa H, et al. Amelanotic metastatic melanomain a patient with oculocutaneous albinism. J Am Acad Dermatol 1993;28:895–900. [PubMed:8491890]Kennedy C, ter Huurne J, Berkhout M, Gruis N, Bastiaens M, Bergman W, et al. Melanocortin 1 receptor(MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largelyindependent of skin type and hair color. J Invest Dermatol 2001;117:294–300. [PubMed: 11511307]Landi MT, Bauer J, Pfeiffer RM, Elder DE, Hulley B, Minghetti P, et al. MC1R germline variants conferrisk for BRAF-mutant melanoma. Science 2006;313:521–522. [PubMed: 16809487]Liu W, Kelly JW, Trivett M, Murray WK, Dowling JP, Wolfe R, et al. Distinct clinical and pathologicalfeatures are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma. J InvestDermatol 2007;127:900–905. [PubMed: 17159915]Meyskens FL Jr, Farmer PJ, Anton-Culver H. Etiologic pathogenesis of melanoma: a unifying hypothesisfor the missing attributable risk. Clin Cancer Res 2004;10:2581–2583. [PubMed: 15102657]Palmer JS, Duffy DL, Box NF, Aitken JF, O'Gorman LE, Green AC, et al. Melanocortin-1 receptorpolymorphisms and risk of melanoma: is the association explained solely by pigmentationphenotype? Am J Hum Genet 2000;66:176–186. [PubMed: 10631149]Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, et al. BRAF and NRAS mutationsin melanoma and melanocytic nevi. Melanoma Res 2006;16:267–273. [PubMed: 16845322]Thomas NE, Edmiston SN, Alexander A, Millikan RC, Groben PA, Hao H, et al. Number of nevi andearly-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer EpidemiolBiomarkers Prev 2007;16:991–997. [PubMed: 17507627]Van Raamsdonk CD, Barsh GS, Wakamatsu K, Ito S. Independent regulation of hair and skin color bytwo G protein-coupled pathways. Pigment Cell Melanoma Res. 2009 Jul 21; [Epub ahead of print].Thomas et al. Page 4J Invest Dermatol. Author manuscript; available in PMC 2011 January 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1. Potential opposing effects of MC1R variant status upon risk of BRAF-mutant melanomaFunctional MC1R allows the production of the darker eumelanin pigment and the tanningresponse. Carriage of decrease-of-function MC1R variants may allow increased BRAF-mutantmelanoma risk through decreased photo-protection by eumelanin and attenuation of DNAdamage response mechanisms. In opposition, more functional MC1R variants may increaserisk through increased eumelanin leading to more oxidative stress and increase sun exposuredue to less sun sensitivity.Thomas et al. Page 5J Invest Dermatol. Author manuscript; available in PMC 2011 January 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Melanoma molecular subtypes: Unifying and paradoxical results

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