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http://www.tandfonline.com/doi/full/10.1080/19381980.2016.1267077
Dianne E. Godar , Ph.D., Madhan Subramanian & Stephen J. Merrill
Article: e1267077 | Received 29 Aug 2016, Accepted 23 Nov 2016, Accepted author version posted online: 14 Dec 2016, Published online: 14 Dec 2016

Because the incidence of cutaneous malignant melanoma (CMM) was reported to increase with increasing terrestrial UVR (290–400 nm) doses in the US back in 1975 and a recent publication showed no association exists with UVR exposure at all, we set out to fully elucidate the role of UVR in CMM. To achieve this goal, we analyzed the CMM incidences over latitude and estimated the average personal UVR dose in the US and numerous countries (> 50) on 5 continents around the world. Using data from the International Agency for Research on Cancer in 2005, we performed worldwide analysis of CMM over UVR dose by sex, age group (0–14, 15–29, 30–49, 50–69, 70–85+) and Fitzpatrick skin types I-VI. Surprisingly, increasing UVR doses, which represent erythemally-weighted doses comprised primarily of UVB (290–315 nm) radiation, did not significantly correlate with increasing CMM incidence for people with any skin type anywhere in the world.

Paradoxically, we found significant correlations between increasing CMM and decreasing UVB dose in Europeans with skin types I-IV. Both Europeans and Americans in some age groups have significant increasing CMM incidences with decreasing UVB dose, which shows UVB is not the main driver in CMM and suggests a possible role for lower cutaneous vitamin D3 levels and UVA (315–400 nm) radiation. CMM may be initiated or promoted by UVA radiation because people are exposed to it indoors through windows and outdoors through some sunscreen formulations. Thus, our findings may explain why some broad-spectrum sunscreen formulations do not protect against getting CMM.

KEYWORDS: aging, DNA Damage, pheomelanin, pigment, skin cancer, Ultraviolet-A, Ultraviolet-B, vitamin D3
Introduction

The incidence of cutaneous malignant melanoma (CMM) has been exponentially increasing over the last several decades in fair-skinned males and females around the world.1,2 Merrill SJ, Ashrafi S, Subramanian M, Godar DE. Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests two major risk factors. Dermato-Endocrinol 2015; 7(1):e1004018; PMID:26413188; http://dx.doi.org/10.1080/19381980.2014.1004018

Godar DE, Landry RJ, Lucas AD. Increased UVA exposures and decreased cutaneous Vitamin D(3) levels may be responsible for the increasing incidence of melanoma. Med Hypotheses 2009; 72:434-443; PMID:19155143; http://dx.doi.org/10.1016/j.mehy.2008.09.056

The exponential increase in CMM may be due to the exponential spread of the Human Papilloma Virus (HPV), the declining levels of vitamin D over recent decades primarily from indoor work, and the increasing UVA (315–400 nm) and visible light (400–700 nm) exposures through windows and sunscreens. HPV may explain the exponential increase in CMM over recent decades because it has also been increasing at an exponential rate3 Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29:4294-301; PMID:21969503; http://dx.doi.org/10.1200/JCO.2011.36.4596
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while vitamin D levels have decreased over the last 5 decades, as reflected by the almost 10-fold increase in the inversely related parathyroid hormone levels.4 Griebeler ML, Kearns AE, Ryu E, Hathcock MA, Melton LJ, 3rd, Wermers RA. Secular trends in the incidence of primary hyperparathyroidism over five decades (1965–2010). Bone 2015; 73:1-7. Epub 2014 Dec 11; PMID:25497786; http://dx.doi.org/10.1016/j.bone.2014.12.003
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Vitamin D is important for a variety of reasons in reducing the risk for getting CMM but one of the most essential is for T cell activation in order to kill virally infected and cancerous cells.5 von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010; 11:344-349; PMID:20208539; http://dx.doi.org/10.1038/ni.1851
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Low cutaneous vitamin D3 levels can occur from intermittent sun exposures and people's perception of having a tendency to burn,6,7 Elwood JM, Gallagher RP, Hill GB, Pearson JC. Cutaneous melanoma in relation to intermittent and constant sun exposure - The Western Canada Melanoma Study. Br J Cancer 1985; 35:427-433

Elwood JM, Gallagher RP, Davison J, Hill GB. Sunburn, suntan and the risk of cutaneous malignant melanoma-The Western Canada Melanoma Study. Br J Cancer 1985; 51:543-549; PMID:3978032; http://dx.doi.org/10.1038/bjc.1985.77

which leads to protective behaviors like avoiding sun exposure and excessive use of sunscreens that increase UVA and visible light doses. Ironically, the sunscreen formulations in the United States (US) that decrease UVB doses and successfully prevent sunburn did not result in a decrease in the incidence of CMM8 Vainio H, Miller AB, Bianchini F. An international evaluation of the cancer-preventive potential of sunscreens. Int J Cancer 2000; 88:838-842; PMID:11072258; http://dx.doi.org/10.1002/1097-0215(20001201)88:5%3c838::AID-IJC25%3e3.0.CO;2-X
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but rather they may have increased CMM in a dose-dependent manner.9 Westerdahl J, Olsson H, Måsbäck A, Ingvar C, Jonsson N. Is the use of sunscreens a risk factor for malignant melanoma? Melanoma Res 1995; 5:59-65; PMID:7734957; http://dx.doi.org/10.1097/00008390-199502000-00007
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Although controversial, the reasons US sunscreens were not protective against CMM may be because they almost completely annihilate vitamin D3 production using sun protection factor of 15 or more10 Matsuoka LY, Wortsman J, Hanifan N, Holick MF. Chronic sunscreen use decreases circulating concentrations of 25-hydroxyvitamin D. A preliminary study. Arch Dermatol 1988; 124:1802-1804; http://dx.doi.org/10.1001/archderm.1988.01670120018003
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and they allow people to stay out in the sun longer resulting in higher doses of UVA radiation and visible light. UVA is suspected to be the driver in CMM because the US broad-spectrum sunscreens did not provide enough protection in the longer waveband regions of UVR (> 380 nm) and they did not protect against getting CMM as did the European broad-spectrum sunscreens11 Diffey B. New Sunscreens and the Precautionary Principle. JAMA Dermatol 2016; 152(5):511-512; PMID:26885870; http://dx.doi.org/10.1001/jamadermatol.2015.6069
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and the Australian broad-spectrum sunscreens given to study participants which did decrease the incidence of CMM by 50%.

CMM has been exponentially increasing exclusively in European-ancestry populations for over 5 decades as revealed by worldwide temporal analysis by sex, age (0–14, 15–29, 30–49, 50–69, 70–85+) and Fitzpatrick skin types I-VI.13,14 Merrill SJ, Madhan Subramanian M, Godar DE. Worldwide cutaneous malignant melanoma incidences analyzed by sex, age, and skin type over time (1955–2007): Is HPV infection of androgenic hair follicular melanocytes a risk factor for developing melanoma exclusively in people of European-ancestry? Dermato-Endocrinol 2016; 8:e1215391; PMID:27588159; http://dx.doi.org/10.1080/19381980.2016.1215391
Fitzpatrick TB. The validity and practicality of Sun-reactive skin types I through VI. Arch Dermatol 1988; 124:869-871; PMID:3377516; http://dx.doi.org/10.1001/archderm.1988.01670060015008

The observed 2 orders of magnitude increase in the CMM incidence between the 2 youngest age groups, 0–14 and 15–29, exclusively in European-ancestry populations indicates a hormonal event occurs during puberty which dramatically increases the incidence of CMM. Some scientists think this might have occurred because children get 3 times the UVR dose that adults get, but that assumption was proven not to be true; in fact, people get about the same exposures throughout their lives.15 Godar DE, Urbach F, Gasparro FP, van der Leun JC. UV doses of young adults. Photochem Photobiol 2003; 77:453-457; PMID:12733658; http://dx.doi.org/10.1562/0031-8655(2003)077%3c0453:UDOYA%3e2.0.CO;2
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So, one important risk factor for CMM may be developing androgenic body hair follicles that are immune privileged sites16 Christoph T, Müller-Röver S, Audring H, Tobin DJ, Hermes B, Cotsarelis G, Rückert R, Paus R. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol 2000; 142:862-873; PMID:10809841; http://dx.doi.org/10.1046/j.1365-2133.2000.03464.x
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of persistent HPV infection.17 Wolf P, Seidl H, Bäck B, Binder B, Höfler G, Quehenberger F, Hoffmann C, Kerl H, Stark S, Pfister HJ, et al. Increased prevalence of human papillomavirus in hairs plucked from patients with psoriasis treated with psoralen-UV-A. Arch Dermatol 2004; 140:317-324; PMID:15023775; http://dx.doi.org/10.1001/archderm.140.3.317
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Additionally, the hormone estrogen, which is involved in hair maintenance,18 Ohnemus U, Uenalan M, Inzunza J, Gustafsson JA, Paus R. The hair follicle as an estrogen target and source. Endocr Rev 2006; 27(6):677-706. Review; PMID:16877675; http://dx.doi.org/10.1210/er.2006-0020
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Most of the risk factors for CMM were determined by epidemiology studies which showed people with fair skin (Fitzpatrick skin type I-III), numerous nevi, and light hair have significantly higher incidences of CMM.20 Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer 2005; 41:2040-2059. Review; PMID:16125929; http://dx.doi.org/10.1016/j.ejca.2005.03.034
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These fair-skinned people also have higher incidences of non-melanoma skin cancers, which unlike CMM occur exclusively on body sites that are chronically exposed to the sun. For example, clinicians have known for over 5 decades that 70–90% of non-melanoma skin cancers occur primarily on body sites chronically exposed to UVR, i.e., the head and neck;21 Urbach F. The Biological Effects of Ultraviolet Radiation with Emphasis on the Skin. 1969 Pergamon, New York: Oxford.
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Males have more CMM on their face, neck, and trunk than females who have more CMM on their lower limbs, which corresponds well with the distribution of androgenic body hair23 Otberg N, Richter H, Schaefer H, Blume-Peytavi U, Sterry W, Lademann J. Variations of hair follicle size and distribution in different body sites. J Invest Dermatol 2004; 122:14-19; http://dx.doi.org/10.1046/j.0022-202X.2003.22110.x
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that HPV can infect16 Christoph T, Müller-Röver S, Audring H, Tobin DJ, Hermes B, Cotsarelis G,

Rückert R, Paus R. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol 2000; 142:862-873; PMID:10809841; http://dx.doi.org/10.1046/j.1365-2133.2000.03464.x
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along with nevi and CMM.24 La Placa M, Ambretti S, Bonvicini F, Venturoli S, Bianchi T, Varotti C,

Zerbini M, Musiani M. Presence of high-risk mucosal human papillomavirus genotypes in primary melanoma and in acquired dysplastic melanocytic naevi. Br J Dermatol 2005; 152:909-914; PMID:15888145; http://dx.doi.org/10.1111/j.1365-2133.2005.06344.x
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Light hair color, especially red hair and nevi are major risk factors for CMM20 Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer 2005; 41:2040-2059. Review; PMID:16125929; http://dx.doi.org/10.1016/j.ejca.2005.03.034
[CrossRef], [PubMed], [Web of Science ®], [Google Scholar] probably because they both contain large amounts of pheomelanin and its early precursor molecules like benzothiazine25 Jimbow K, Lee SK, King MG, Hara H, Chen H, Dakour J, Marusyk H. Melanin pigments and melanosomal proteins as differentiation markers unique to normal and neoplastic melanocytes. J Invest Dermatol 1993; 100:259S-268S. Review; PMID:8440900; http://dx.doi.org/10.1038/jid.1993.47
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that absorb UVA1 radiation (341–400 nm; λmax > 340 nm).

Because the incidence of CMM was reported to increase with increasing terrestrial UVR doses in the US back in 197526 and a recent report found no association with UVR exposure at all,27 Fleischer AB, Jr, Fleischer SE. Solar radiation and the incidence and mortality of leading invasive cancers in the United States. Dermatoendocrinol 2016; 8(1):e1162366. eCollection 2016 Jan-Dec; PMID:27195056; http://dx.doi.org/10.1080/19381980.2016.1162366
[Taylor & Francis Online], [Google Scholar] we set out to fully elucidate the role of UVR in CMM. To achieve this goal, we analyzed the CMM incidences over latitude and estimated the average personal UVB dose of males and females in 5 age groups (0–14, 15–29, 30–49, 50–69, 70–85+ yr.) with all skin types I-VI in the US and numerous countries (>50) on 5 continents around the world.

Discussion

For the first time, we provide comprehensive worldwide analyses of CMM incidences over personal UVB doses for males and females in 5 age groups (0–14, 15–29, 30–49, 50–69, 70–85+ yr.) with all Fitzpatrick skin types I-VI14 Fitzpatrick TB. The validity and practicality of Sun-reactive skin types I through VI. Arch Dermatol 1988; 124:869-871; PMID:3377516; http://dx.doi.org/10.1001/archderm.1988.01670060015008
[CrossRef], [PubMed], [Web of Science ®], [Google Scholar] on 5 continents around the world. Contrary to popular belief, no evidence exists for a significant trend or correlation between the increasing incidences of CMM and increasing personal UVB dose for males or females of any age group or skin type I-VI anywhere in the world (Fig. 1–3 and Table 1). We did find an apparent correlation between CMM incidence and UVB dose in the US back in 1975 (results not shown), in agreement with previous findings.26 Fears TR, Scotto J, Schneiderman MA. Skin cancer, melanoma, and sunlight. Am J Public Health 1976; 66:461-464; PMID:1275120; http://dx.doi.org/10.2105/AJPH.66.5.461
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However, those observations may be misleading because IARC only had data for 10 states in 1975 (12 regions; 3 in California) and the previous study only analyzed data for 9 states compared with our analysis here in 2005 for 44 out of 50 states, which confirms another recent US analysis that used another database and approach.27 Fleischer AB, Jr, Fleischer SE. Solar radiation and the incidence and mortality of leading invasive cancers in the United States. Dermatoendocrinol 2016; 8(1):e1162366. eCollection 2016 Jan-Dec; PMID:27195056; http://dx.doi.org/10.1080/19381980.2016.1162366
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Counter intuitively, in Europe, we found a significant correlation exists between decreasing UVB doses and increasing CMM for fair-skinned, skin type I-III females over 29 y. (Fig. 1A right panels; p < 0.05, Table 1). In addition, we found a very significant correlation exists between decreasing UVB doses and increasing CMM for skin type III-IV Italian males and females over 29 y. (Fig. 3 left panels; p < 0.001, Table 1). Our European findings here are in agreement with our previous analysis for the year 2000 where we found both sexes in all age groups had a significant correlation between increasing CMM incidence and decreasing UVB dose.1 Merrill SJ, Ashrafi S, Subramanian M, Godar DE. Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests two major risk factors. Dermato-Endocrinol 2015; 7(1):e1004018; PMID:26413188; http://dx.doi.org/10.1080/19381980.2014.1004018
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Besides decreasing levels of vitamin D3 with decreasing UVB dose or increasing latitude,1,2 Merrill SJ, Ashrafi S, Subramanian M, Godar DE. Exponentially increasing incidences of cutaneous malignant melanoma in Europe correlate with low personal annual UV doses and suggests two major risk factors. Dermato-Endocrinol 2015; 7(1):e1004018; PMID:26413188; http://dx.doi.org/10.1080/19381980.2014.1004018
Godar DE, Landry RJ, Lucas AD. Increased UVA exposures and decreased cutaneous Vitamin D(3) levels may be responsible for the increasing incidence of melanoma. Med Hypotheses 2009; 72:434-443; PMID:19155143; http://dx.doi.org/10.1016/j.mehy.2008.09.056

another explanation may be increasing red hair gene variants of MC1R with increasing latitude. However, a significant increasing CMM incidence with increasing latitude only began to occur in Europe after 1960 with no corresponding change in the population's hair distribution, so that decreasing vitamin D levels appears to be a more feasible explanation for this observation.

The fact that we did not find a correlation between increasing CMM and increasing UVB doses for males or females in any age group or skin type I-VI on any continent or country around the world suggests that unlike non-melanoma skin cancers, UVB radiation does not play an important role in the etiology of human CMM. If UVB were responsible for initiating melanoma, we would expect any sunscreen formulation to protect against getting CMM because they all prevent sunburn by screening out UVB, but we do not observe this.11 Diffey B. New Sunscreens and the Precautionary Principle. JAMA Dermatol 2016; 152(5):511-512; PMID:26885870; http://dx.doi.org/10.1001/jamadermatol.2015.6069
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Thus, our results in combination with the sunscreen findings allows us to rule out a major role for UVB radiation or sunburns initiating human CMM, in agreement with other studies.27,36 Fleischer AB, Jr, Fleischer SE. Solar radiation and the incidence and mortality of leading invasive cancers in the United States. Dermatoendocrinol 2016; 8(1):e1162366. eCollection 2016 Jan-Dec; PMID:27195056; http://dx.doi.org/10.1080/19381980.2016.1162366
Kavouras I, Gomez T, Chalbot MC. UVA and cutaneous melanoma incidences: spatial patterns and communities at risk. J Environ Health 2015; 77:8-14; PMID:25985533

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Grigalavicius M, Moan J, Dahlback A, Juzeniene A. Daily, seasonal, and latitudinal variations in solar ultraviolet A and B radiation in relation to vitamin D production and risk for skin cancer. Int J Dermatol 2016; 55:e23-e28; PMID:26547141; http://dx.doi.org/10.1111/ijd.13065
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HPV can also create these C→T transition mutations via its E2 protein because it causes production of ROS by adversely interacting with the mitochondria.55 Lai D, Tan CL, Gunaratne J, Quek LS, Nei W, Thierry F, Bellanger S.. Localization of HPV-18 E2 at mitochondrial membranes induces ROS release and modulates host cell metabolism. PLoS One 2013; 8(9):e75625. eCollection 2013; PMID:24086592; http://dx.doi.org/10.1371/journal.pone.0075625
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In addition to transition mutations, clinicians find unique transversion mutations from photoadduct formation47 Peritz AE, Gasparro FP. Psoriasis, PUVA, and skin cancer-molecular epidemiology: the curious question of T→A transversions. J Investig Dermatol Symp Pro 1999; 4:11-16. Review; http://dx.doi.org/10.1038/sj.jidsp.5640174
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in CMM after therapeutic PUVA (8-methoxypsoralen and UVA).48 Stern RS. PUVA Follow up Study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001; 44:755-761; PMID:11312420; http://dx.doi.org/10.1067/mjd.2001.114576
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in BRAFV600E may also be UVA-induced from photoadduct formation between a red-pigment pheomelanin precursor molecule like benzothiazine (λmax>340 nm) crosslinking to a thymine base, similar to how adduct formation occurs during PUVA.47,48 Peritz AE, Gasparro FP. Psoriasis, PUVA, and skin cancer-molecular epidemiology: the curious question of T→A transversions. J Investig Dermatol Symp Pro 1999; 4:11-16. Review; http://dx.doi.org/10.1038/sj.jidsp.5640174
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Besides the DNA damage caused by chemical crosslinks forming photoadducts and ROS causing deamination of cytosines, epigenetic events like methylation of cytosines can also result in deamination leading to C→T transition mutations.54 Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 2003; 17(10):1195-214; PMID:12832285; http://dx.doi.org/10.1096/fj.02-0752rev
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Other than the UV nonsignature transversion T→A mutation in BRAFV600E, CMM somatic mutations consist almost entirely of C→T transition mutations occurring predominately at NpCpG trinucleotide sites, which are signature mutations shared with cervical cancer.57 Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL, et al. Signatures of mutational processes in human cancer. Nature 2013; 500(7463):415-21. Epub 2013 Aug 14. Erratum in: Nature. 2013;502(7470):258; PMID:23945592; http://dx.doi.org/10.1038/nature12477
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HPV causes cervical cancer, which is associated with its own signature mutations, specifically the APOBEC3B-mediated cytosine deaminations leading to C→T (or G) mutations.58 Henderson S, Chakravarthy A, Su X, Boshoff C, Fenton TR. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep 2014; 7(6):1833-41. Epub 2014 Jun 5; PMID:24910434; http://dx.doi.org/10.1016/j.celrep.2014.05.012
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These C→T transition mutations are specific for HPV+ tumors as they are only found in cervical and HPV+ oropharyngeal cancers; they are not found in HPV- oropharyngeal cancer or liver cancers associated with Hepatitis B or C. HPV causes deamination of methylated cytosines leading to C→T transition mutations in CDKN2A, a gene that codes for the tumor suppressor proteins p16 and p14arf, which is associated with HPV+ oropharyngeal and cervical cancers.59,60 Schlecht NF, Ben-Dayan M, Anayannis N, Lleras RA, Thomas C, Wang Y, Smith RV, Burk RD, Harris TM, Childs G, et al. Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma. Cancer Med 2015; 4(3):342-53. Epub 2015 Jan 26; PMID:25619363; http://dx.doi.org/10.1002/cam4.374
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Intriguingly, a C→T polymorphism in CDKN2A is also methylated in CMM.61 Straume O, Smeds J, Kumar R, Hemminki K, Akslen LA. Significant impact of promoter hypermethylation and the 540 C>T polymorphism of CDKN2A in cutaneous melanoma of the vertical growth phase. Am J Pathol 2002; 161(1):229-237; PMID:12107107; http://dx.doi.org/10.1016/S0002-9440(10)64174-0
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These C→T transition mutations appear to be increasing over time exclusively in the European-ancestry germline.62 Harris K. Evidence for recent, population-specific evolution of the human mutation rate. Proc Natl Acad Sci U S A 2015 Mar 17; 112(11):3439-44. Epub 2015 Mar 2; PMID:25733855; http://dx.doi.org/10.1073/pnas.1418652112
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UVR cannot penetrate deeply enough to result in germline mutations while viruses can; and scientists find HPV in sperm.63 Kaspersen MD, Larsen PB, Ingerslev HJ, Fedder J, Petersen GB, Bonde J, Höllsberg P.. Identification of multiple HPV types on spermatozoa from human sperm donors. PLoS One 2011 Mar 29; 6(3):e18095; PMID:21479232; http://dx.doi.org/10.1371/journal.pone.0018095
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Thus, the so-called UVB signature mutations found in CMM that are almost always C→T transition mutations may actually be created by ROS produced during pheomelanin synthesis, UVA/Visible exposure, or HPV infection, the latter of which can also cause methylation of cytosines resulting in deamination of cytosine and C→T mutations.

Animal studies showing UVB radiation initiates CMM may be deceiving due to the superficial location of their follicular melanocytes (epidermal thickness of about 20µm) compared with human (epidermal thickness of about 80µm)64 Gambichler T, Matip R, Moussa G, Altmeyer P, Hoffmann K. In vivo data of epidermal thickness evaluated by optical coherence tomography: effects of age, gender, skin type, and anatomic site. J Dermatol Sci 2006; 44:145-152; PMID:17071059; http://dx.doi.org/10.1016/j.jdermsci.2006.09.008
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allowing UVB to irradiate their bulge regions but not the human follicular melanocytes located between 362µm for vellus and 1,161µm for terminal bulge regions.65 Meinhardt M, Krebs R, Anders A, Heinrich U, Tronnier H. Wavelength-dependent penetration depths of ultraviolet radiation in human skin. J Biomed Opt 2008; 13:044030; PMID:19021357; http://dx.doi.org/10.1117/1.2957970
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However, about 1% of the incident UVA1 radiation (341–400 nm) can penetrate into the subcutaneous layer of the skin irradiating all follicular regions including the root bulb of terminal hair (1,000–5,000µm).66 Bruls WA, Slaper H, van der Leun JC, Berrens L. Transmission of human epidermis and stratum corneum as a function of thickness in the ultraviolet and visible wavelengths. Photochem Photobiol 1984; 40:485-494; PMID:6505037; http://dx.doi.org/10.1111/j.1751-1097.1984.tb04622.x
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Thus, if UVR plays any significant role in human CMM, it has to be UVA rather than UVB radiation.

In order to help elucidate the potential role of UVA in CMM, we surveyed epidemiology studies for clues. Most epidemiology studies found light haired, especially red-haired people have significantly higher incidences of CMM than darker-haired people do, which meta-analysis confirmed.20 Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, Boyle P, Melchi CF. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer 2005; 41:2040-2059. Review; PMID:16125929; http://dx.doi.org/10.1016/j.ejca.2005.03.034
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A recent epidemiology study revealed a significant increase in the CMM risk exists between European people with light blond/red hair and European people with dark brown/black hair (p = 5.96 × 10−6).67 Kosiniak-Kamysz A, Marczakiewicz-Lustig A, Marcińska M, Skowron M, Wojas-Pelc A, Pośpiech E, Branicki W. Increased risk of developing cutaneous malignant melanoma is associated with variation in pigmentation genes and VDR, and may involve epistatic effects. Melanoma Res 2014; 24:388-96; PMID:24926819; http://dx.doi.org/10.1097/CMR.0000000000000095
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Meta-analysis of the melanocortin-1-receptor and CMM risk revealed 3 variants associated with only red hair that gave significant increased risks for CMM with odds ratios ranging from 2.99 to 8.10.68 Raimondi S, Sera F, Gandini S, Iodice S, Caini S, Maisonneuve P, Branicki W.. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer 2008; 122:2753-2760; PMID:18366057; http://dx.doi.org/10.1002/ijc.23396
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Moreover, in the absence of UVR exposure, regardless of their epidermal melanocyte status ( ± ), black and albino C57BL/6 mice on a mutated BRAFV600E background developed similarly low rates of CMM after a long latency period, whereas over half the mice with red hair developed melanomas after only a year.69 Mitra D, Luo X, Morgan A, Wang J, Hoang MP, Lo J, Guerrero CR, Lennerz JK, Mihm MC, Wargo JA. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature 2012; 491:449-453. Epub 2012 Oct 31; PMID:23123854; http://dx.doi.org/10.1038/nature11624
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Recently, scientists confirmed the human variants of the MC1R red hair gene dramatically increase the risk for getting CMM independent of UVR exposure.70 Wendt J, Rauscher S, Burgstaller-Muehlbacher S, Fae I, Fischer G, Pehamberger H, Okamoto Human Determinants and the Role of Melanocortin-1 Receptor Variants in Melanoma Risk Independent of UV Radiation Exposure. JAMA Dermatol 2016; 152:776-782; PMID:27050141; http://dx.doi.org/10.1001/jamadermatol.2016.0050
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and have eumelanin to pheomelanin ratios of only 1.46 and 4.44, respectively, while wild types have 5.81 (p < 0.001).72 Naysmith L, Waterston K, Ha T, Flanagan N, Bisset Y, Ray A, Wakamatsu K, Ito S, Rees JL. Quantitative measures of the effect of the melanocortin 1 receptor on human pigmentary status. J Invest Dermatol 2004; 122:423-428; PMID:15009725; http://dx.doi.org/10.1046/j.0022-202X.2004.22221.x
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These findings highlight the fact that people with dark hair and certain melanocortin-1-receptor variants can also get CMM.73 Kanetsky PA, Panossian S, Elder DE, Guerry D, Ming ME, Schuchter L, Rebbeck TR. Does MC1R genotype convey information about melanoma risk beyond risk phenotypes? Cancer 2010; 116:2416-2428; PMID:20301115
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Pheomelanin has been detected in normal unexposed skin and its synthesis is markedly increased in dysplastic melanocytic nevi and melanoma cells to the point where high levels of its metabolites have been detected in patients' urine.25 Jimbow K, Lee SK, King MG, Hara H, Chen H, Dakour J, Marusyk H.

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Unlike eumelanin synthesis, pheomelanin synthesis produces ROS and its cysteine-related precursors like benzothiazine, benzothiazinylalanine and similar precursor molecules that absorb UVA1 radiation (λmax>340 nm)74 Napolitano A, De Lucia M, Panzella L, d'Ischia M. The “benzothiazine” chromophore of pheomelanins: a reassessment. Photochem Photobiol 2008; 84:593-599; PMID:18435615; http://dx.doi.org/10.1111/j.1751-1097.2007.00232.x
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probably also play significant roles in the etiology of CMM.

The most important evidence that some kind of melanin is crucial for developing melanoma comes from studies showing albino blacks almost exclusively do not get CMM while they do get numerous, early onset non-melanoma skin cancers and they also sunburn easily.75,76 Grønskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis 2007; 2:43; PMID:17980020; http://dx.doi.org/10.1186/1750-1172-2-43
Kiprono SK, Chaula BM, Beltraminelli H. Histological review of skin cancers in African Albinos: a 10-year retrospective review. BMC Cancer 2014; 14:157. Review; PMID:24597988; http://dx.doi.org/10.1186/1471-2407-14-157

Albino blacks with white skin and white hair have the same number of melanocytes as normal people with pigmented skin and hair but they do not usually produce any melanin or its precursor molecules revealing 2 important risk factors involved in non-melanoma skin cancers are not involved in CMM, i.e., skin color and conventional UVR-induced DNA damage such as cyclobutane pyrimidine dimers and 8-hydroxy-2'-deoxyguanosine. Like whites, albino blacks get the same UV-induced DNA damage that keratinocytes accumulate, as shown by their higher rates of non-melanoma skin cancer at younger ages, but those DNA lesions do not transform their melanocytes. The fact that all 4 types of albinos, OCA1 (A&B), OCA2, OCA3, and OCA4 have drastically reduced production of melanin and its precursors76 Kiprono SK, Chaula BM, Beltraminelli H. Histological review of skin cancers in African Albinos: a 10-year retrospective review. BMC Cancer 2014; 14:157. Review; PMID:24597988; http://dx.doi.org/10.1186/1471-2407-14-157
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and have an almost non-existent incidence of CMM suggests that either melanin or its precursors are probably required for initiating melanoma. Strong evidence that melanoma initiation relies upon melanin content comes from the fact that the action spectrum for melanoma in a fish model (Xiphophorus) is identical to the action spectrum for photosensitized radicals that are only produced by the pigmented fish.77 Wood SR, Berwick M, Ley RD, Walter RB, Setlow RB, Timmins GS. UV causation of melanoma in Xiphophorus is dominated by melanin photosensitized oxidant production. Proc Natl Acad Sci U S A 2006; 103:4111-4115; PMID:16537493; http://dx.doi.org/10.1073/pnas.0511248103
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Conclusions

A working hypothesis must explain why the incidence of CMM is similar between outdoor and indoor workers when the former gets 3–10 times the UVR dose that the latter gets (see Fig. 4). Unlike indoor workers, who are only exposed to UVA radiation through windows,2 Godar DE, Landry RJ, Lucas AD. Increased UVA exposures and decreased cutaneous Vitamin D(3) levels may be responsible for the increasing incidence of melanoma. Med Hypotheses 2009; 72:434-443; PMID:19155143; http://dx.doi.org/10.1016/j.mehy.2008.09.056
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along with visible light, outdoor workers are exposed to UVA and UVB as well as visible light. Because UVB immediately crosslinks adjacent thymine bases, it prevents UVA from crosslinking other molecules like benzothiazine to the thymine bases, which is similar to PUVA's 8-methoxypsoralen bulky adduct that is difficult to repair. Thus, to prevent skin cancer, and especially melanoma, we apparently need sunscreens with not only UVB protection but with better broad-spectrum protection in the UVA and even in the visible waveband region.78,79 Liebel F, Kaur S, Ruvolo E, Kollias N, Southall MD. Irradiation of skin with visible light induces reactive oxygen species and matrix-degrading enzymes. J Invest Dermatol 2012 Jul; 132(7):1901-7; PMID:22318388; http://dx.doi.org/10.1038/jid.2011.476
Zastrow L, Lademann J. Light - Instead of UV Protection: New requirements for skin cancer prevention. Anticancer Res 2016; 36(3):1389-93. Review; PMID:26977040


Figure 4. The consequences of DNA photoproduct damage from exposure to outdoor UVA and UVB radiation versus indoor UVA radiation. Outdoor sunshine has both UVA and UVB radiation vs. indoor sunshine that has only UVA radiation because, unlike UVB, it can pass through window glass. The outdoor UVB radiation causes efficient pyrimidine dimer formation and UVA makes benzothiazine or benzothiazinylalanine and other radicals (λmax >340 nm) that cannot react with the pyrimidine dimers formed outdoors because the covalent bonds block the available reaction sites (competitive reaction); whereas, indoor UVA forms few dimers so that many pyrimidine sites are available to react with the benzothiazine radicals it forms. Besides UVA creating ROS that oxidizes deoxyguanosine to 8-oxodG (G = O in diagram), UVA can create ONOO- radicals that can also make CPD in the dark for several hours post exposure [80].
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