Etiology Of Melanoma Research Articles

The role of germline alterations in the DNA damage response genes BRIP1 and BRCA2 in melanoma susceptibility.

We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety-two high-risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell-cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology. © 2016 Wiley Periodicals, Inc.

Melanoma and Human Papillomaviruses: Is There an Outlook for Study?

Melanoma is one of the most aggressive human malignant tumors. Its incidence and mortality are growing steadily. Ultraviolet irradiation is the main risk factor for melanoma involved in melanomagenesis. The probability of viral etiology of melanoma has been discussed. Human papillomaviruses (HPV) have been mentioned among candidates for its etiologic agents because some HPV types are the powerful carcinogens causing cervical cancer and other cancers. The review analyses the literature data on the association of melanoma with HPV Several groupsfound HPVin skin melanomas as well as in mucosa; viruses of high oncogenic risk were detected in some cases. For some organs the etiological role of high-risk HPV as inducers of invasive carcinomas is confirmed. These organs require special mention: cervix uteri, vulva, vagina, penis, anal region, and oral cavity. However in the majority of the studies in which viral DNA-positive melanomas were found, testing for viral genome expression was not done while this is the fact of primary importance. HPVare found in normal skin and mucous membranes thus creating justifiable threat of tumor specimen contamination with viral DNA in vivo. There are limited data on aggravation of the disease prognosis in papillomavirus-positive melanomas. However, any systematic observation of a sizeable patient group distinguished by that tumor type has not been performed yet. Viral E6 and E7 oncogenes of high-risk papillomaviruses were shown to be able to transform normal human melanocytes in vitro experiments. Thus, we can assume the presence of the association of melanoma with oncogenic HPV. The clinical significance of this problem is indisputable under the conditions of the steady increase in melanoma incidence and mortality rates in Russia and abroad. The problem requires further study.

Effect of Adipocyte Secretome in Melanoma Progression and Vasculogenic Mimicry.

Obesity, favored by the modern lifestyle, acquired epidemic proportions nowadays. Obesity has been associated with various major causes of death and morbidity including malignant neoplasms. This increased prevalence has been accompanied by a worldwide increase in cutaneous melanoma incidence rates during the last decades. Obesity involvement in melanoma aetiology has been recognized, but the implicated mechanisms remain unclear. In the present study, we address this relationship and investigate the influence of adipocytes secretome on B16-F10 and MeWo melanoma cell lines. Using the 3T3-L1 adipocyte cell line, as well as ex vivo subcutaneous (SAT) and visceral (VAT) adipose tissue conditioned medium, we were able to show that adipocyte-released factors play a dual role in increasing melanoma cell overall survival, both by enhancing proliferation and decreasing apoptosis. B16-F10 cell migration and cell-cell and cell-matrix adhesion capacity were predominantly enhanced in the presence of SAT and VAT released factors. Melanocytes morphology and melanin content were also altered by exposure to adipocyte conditioned medium disclosing a more dedifferentiated phenotype of melanocytes. In addition, exposure to adipocyte-secreted molecules induced melanocytes to rearrange, on 3D cultures, into vessel-like structures, and generate characteristic vasculogenic mimicry patterns. These findings are corroborated by the released factors profile of 3T3-L1, SAT, and VAT assessed by microarrays, and led us to highlight the mechanisms by which adipose secretome from sub-cutaneous or visceral depots promote melanoma progression. J. Cell. Biochem. 117: 1697-1706, 2016. © 2015 Wiley Periodicals, Inc.

Is UV an etiological factor of acral melanoma?

Ultraviolet (UV) radiation is a major environmental risk factor for melanoma, particularly among Caucasians. However, studies have generated conflicting results on the role of UV exposure in the development of acral melanoma, the most prevalent subtype of melanoma in non-Caucasians. In this review, we analyzed studies that have examined the relationship between acral melanoma and UV and show that acral melanoma has specific epidemiological and genetic characteristics, with a lower frequency or absence of UV-induced features. Therefore, we postulate that UV is probably not involved in the etiology of acral melanoma. However, further epidemiological and laboratory studies are required to fully address this controversial issue, which may lead to a better understanding of the pathogenesis and prevention of acral melanoma.

Molecular genetic response of Xiphophorus maculatus–X. couchianus interspecies hybrid skin to UVB exposure

The phenotypic and genetic similarities between Xiphophorus and human melanoma render Xiphophorus a useful animal model for studying the genetic basis of melanoma etiology. In the Xiphophorus model, melanoma has been shown to be inducible by ultraviolet light (UVB) exposure among interspecies hybrids, but not in parental line fish similarly treated. This leads to questions of what genes are responsive to UVB exposure in the skin of the interspecies hybrids, as well as how parental alleles in hybrids may be differentially regulated and the potential roles they may play in induced melanomagenesis. To address these questions, we produced X. maculatus Jp 163 B×X. couchianus (Sp-Couch) F1 hybrid fish, exposed both hybrid and parental fish to UVB, and performed gene expression profiling of the skin using RNA-Seq methodology. We characterized a group of unique UVB-responsive genes in Sp-Couch hybrid including dct, pmela, tyr, tyrp1a, slc2a11b, rab38a, rab27, tspan10, slc45a2, oca2, slc24a5, ptn and mitfa. These genes are associated with melanin production and melanocyte proliferation. They were also up-regulated in Sp-Couch hybrid, indicating that their UVB response is hybridization initiated. In the hybrid, several melanin production and pigmentation related genes, including slc45a2, tspan10, dct, slc2a11b and ptn showed either X. couchianus or X. maculatus allele specific expression. The finding that these genes exhibit allele specific expression regulatory mechanisms in Sp-Couch hybrids, but do not exhibit a corresponding UVB response in either one of the parental fishes, may suggest UVB targets and imply mechanisms regarding the susceptibility of Sp-Couch to induced melanomagenesis.

Diet Quality and Risk of Melanoma in an Italian Population1–3

Background: Some results from laboratory and epidemiologic studies suggest that diet may influence the risk of melanoma, but convincing evidence for a role of single nutrients or food items is lacking. Diet quality, which considers the combined effect of multiple food items, may be superior for examining this relation.Objective: We sought to assess whether diet quality, evaluated with the use of 4 different dietary indexes, is associated with melanoma risk.Methods: In this population-based case-control study, we analyzed the relation between 4 diet quality indexes, the Healthy Eating Index 2010 (HEI-2010), Dietary Approaches to Stop Hypertension (DASH) index, Greek Mediterranean Index (GMI), and Italian Mediterranean Index (IMI), and melanoma risk in a northern Italian community, with the use of data from 380 cases and 719 matched controls who completed a semiquantitative food frequency questionnaire.Results: In the overall sample, we found an inverse association between disease risk and the HEI-2010 and DASH index, but not the Mediterranean indexes, adjusting for potential confounders (skin phototype, body mass index, energy intake, sunburn history, skin sun reaction, and education). However, in sex stratified analyses, the association appeared only in women (P-trend: 0.10 and 0.04 for the HEI-2010 and DASH index, respectively). The inverse relations were stronger in women younger than age 50 y than in older women, for whom the GMI and IMI scores also showed an inverse association with disease risk (P-trend: 0.05 and 0.02, respectively).Conclusions: These results suggest that diet quality may play a role in cutaneous melanoma etiology among women.

Abstract IA09: What's new in melanoma etiology?

Abstract Melanoma (CM) incidence continues to increase in the US, Europe, and Australia. A concern has been raised whether this is a true increase of CM or a major increase in over diagnosis of CM. Data cited in support of over diagnosis are that mortality rates have not increased proportionately. Another explanation of disproportionate incidence and mortality is that as CM has become more common and both care providers and the general population are more aware of CM, lesions are identified and removed much earlier, leading to better long-term prognosis. In the US, the 5-year relative survival has increased from 81.8% in 1975 to 92.8% in 2006. The distribution of CM differs between men and women; recent data in the U.S. have shown a distinct increase in CM on the trunk of young women, consistent with tanning (Bradford PT et al., CEBP 2010; 19:2410-6). In 2011, there were 960,231 individuals with CM in the US who are at 8.8-fold increased risk of a second primary CM. The major risk factors for CM include genetic susceptibility (covered in detail by Nick Hayward in this session) and ultraviolet exposure. The major high risk susceptibility genes, CDKN2A and CDK4, were identified in the mid-nineties; mutations in either confer similar risks for CM and similar clinical features. More recently, mutations in POT1 were identified in melanoma-prone families using exome sequencing (Robles-Espinoza CD et al., Nat Genet 2014; 46:478-81; Shi J, et al., Nat Genet 2014; 46:482-6). Other rare high risk susceptibility genes will likely be identified. Genome-wide association studies have identified a number of common variants associated with CM; the causal variants marked by the association signals are in large part still being identified. Nevi, particularly dysplastic nevi, are major host susceptibility factors, but nevus genes have been quite challenging to identify. Using a candidate gene approach, Liang et al. identified variants in CDK6 and XRCC1 that were associated with dysplastic nevi, but not CM (J Invest Derm 2014;134:481-7). Ultraviolet radiation exposure is causal for CM, whether from the sun or artificial lights. Tanning is a complex behavior, and it is difficult to separate the risks associated with outdoor and indoor tanning since most who tan use both sources. Wehner et al. conducted a systematic review and metaanalysis of the prevalence of indoor tanning and found that 35.7% (95% CI 27.5%-44.0%) of adults, 55.0% (33.0%-77.1%) of university students and 19.3% (14.7%-24.0%) of adolescents had ever used indoor tanning (JAMA Dermatol 2014;150:390-400). The prevalences varied also by geographic area and sex. Due to the high exposure rates, particularly in adolescents, parts of Europe, Australia, and North America have passed legislation limiting access by adolescents to indoor tanning. There is also a growing body of evidence that UV exposure may be addictive (Heckman CJ et al., Am J Health Promo 2014;28:168-174). The role of screening for CM has been controversial. In 2009, the USPSTF guidelines did not recommend population-based screening for CM. This year, they are reconsidering the issue, in part because of a public health effort in Germany, where screening for skin cancer was made available for adults over 20 (Katalinic A et al., Cancer, 2012; 118:5395-402). In an observational study, melanoma mortality declined by 47% for men and 49% for women in the screened population. Screening may yield higher benefits in recognized at risk groups (Moloney FJ et al. JAMA Dermatol 2014.514). A number of melanoma risk assessment tools could be useful in prioritizing screening, but have not been fully validated (Vuong K et al; JAMA Dermatol 2014;150:434-444). Citation Format: Margaret A. Tucker. What's new in melanoma etiology? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA09.

Gender difference in the association of melanoma etiology to solar UV exposure.

e20012 Background: UV radiation has been considered the major environmental causative factor for melanoma. Our previous limited epidemiologic study suggested additional causative factors for early ...

Abstract 1297: The heritability of melanoma differs between light- and dark-skinned individuals of European descent

Abstract Melanoma is strongly associated with exposure to ultraviolet radiation (UV). The prevalence of melanoma is much higher in lighter-skinned Caucasians as compared to darker-skinned Caucasians who have a higher concentration of melanin in their skin which absorbs UV radiation and prevents it from reaching deeper layers of the skin to cause DNA damage. This suggests that the relative contributions of genes and environment in the etiology of melanoma and the genetic architecture of melanoma susceptibility may differ between these two groups. To test this hypothesis, we assessed the heritability of melanoma separately in self-reported light- and dark-skinned Caucasians using data from a previously published melanoma GWAS of 2000 cases and 1000 controls (Amos et al, 2011). Employing the GCTA method developed by Visscher et al (Yang et al, 2011), which estimates the additive genetic contributions of all genotyped single nucleotide polymorphisms (SNPs) to phenotypic variance, we observed that melanoma was highly heritable in dark-skinned Caucasians (h2 = 66%, SE = 25%, p = 0.0058), but not significantly heritable in light-skinned Caucasians (h2 = 15%, SE = 22%, p = 0.25). This suggests that whereas inherited common genetic variation contributes significantly to melanoma susceptibility in dark-skinned Caucasians, this is not the case in lighter-skinned Caucasians. To determine the consequences of this difference in heritability on melanoma risk, we investigated the enrichment of expression quantitative trait loci (eQTLs) separately in light-skinned Caucasians and dark-skinned Caucasians using a permutation-based strategy. We generated 1000 permutations of the melanoma GWAS, shuffling case-control status each time. In each of the permuted datasets, we calculated the percentage of significant disease-associated variants that are also eQTLs. Then we compared the actual percentage of GWAS hits that are eQTLs to the expected percentage under the null based on the permutations to assess whether there is a significant enrichment of functional variants in the GWAS. We found a significant enrichment of skin and lymphoblastoid cell line (LCL) eQTLs in among the melanoma-associated SNPs (p < 10-4) in the GWAS of light-skinned but not dark-skinned Caucasians. Furthermore the target genes of these eQTLs showed a functional enrichment of response pathways to ultraviolet radiation (UV), the major cause of melanoma. Taken together, these findings indicate that melanoma susceptibility not only has varying contributions of genes and environment but also different genetic architectures in light- vs dark- Caucasians. More broadly, heritability can provide important insights into variable contributions of genetics and environment to cancer and other complex diseases, and can be used to divide patients into genetically homogenous subsets to maximize power to detect significant genotype-disease associations. Citation Format: Imge Hulur, Andrew Skol, Kenan Onel. The heritability of melanoma differs between light- and dark-skinned individuals of European descent. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2014-1297

Abstract 3418: Rare germline copy number variations in hereditary cutaneous melanoma

Abstract Background: Melanoma is a highly aggressive skin cancer; approximately 10% of melanomas are caused by germline mutations, mainly affecting the p16 isoform of the CDKN2A gene (responsible for up to 40% of the familial melanoma). Although other genes exhibiting moderate to high penetrant mutations have been recently associated with melanoma susceptibility, such as CDK4, PALB2, MITF, and TERT promoter, the majority of the melanoma susceptibility remains without a clear genetic etiology. Copy number variations (CNVs) are a common class of structural variants of the human genome, mainly impacting genes that mediate the interaction with environment. However, many rare germline CNVs have been causally associated with diseases, including mental impairment and cancer predisposition. Objective: Aiming to identify new genes potentially related to melanoma predisposition, 34 melanoma-prone patients negative for CDKN2A/CDK4 mutations were investigated for rare germline CNVs. Material and Methods: Patients - patients were ascertained at the A. C. Camargo Cancer Center, Sao Paulo, Brazil; signed informed consents were obtained from all patients. DNA samples from peripheral blood were extracted from 34 unrelated probands fulfilling either the classical criteria for familial melanoma syndrome or based on evidence of a strong genetic predisposition (occurrence of ≥2 primary melanomas). These patients had been previously tested negative for CDKN2A and CDK4 genes. Methods - we performed evaluation of germline CNVs using the CytoSNP-850K (Illumina), analyzing data in the BlueFuse Multi Software v3.2. Selected CNVs were validated by real-time quantitative PCR (qPCR). Results: Among the 34 patients, we detected rare CNVs in 9 of them, mainly large duplications (>230kb) at 4q26-q27, 6p22.1, 8q23.1, 9p24.2, 10q22.3, 12p12.3 and 20p12.1, and deletions affecting 6p24.3 and 19p13.3. Four of these changes in DNA copy number were validated by qPCR using probes for genes mapped within affected regions (ANXA11, ESF1, MGST1 and ANGPT1 genes). Conclusion: We found 26% of the melanoma-prone patients carrying rare germline CNVs that encompass genes potentially associated with melanoma predisposition. Our data suggest that melanoma susceptibility could be originated by a broad spectrum of no recurrent genomic alterations, and part of the genetic etiology of the hereditary melanoma might reside in rare germline copy number changes. In addition to the well-known melanoma genes, germline CNVs, here reported, disclosed other candidate genes to melanoma predisposition deserving further investigation. Funding: This work was supported by grants from FAPESP (2012/21932-6) and the Brazilian National Institute of Science and Technology in Oncogenomics (FAPESP 2008/57887-9, CNPq 573589/08-9). Citation Format: Felipe Fidalgo, Tatiane Rodrigues, Amanda Gonçalves Silva, Luciana Facure, Amanda Nóbrega, Bianca Sá, João Pereira Duprat, Maria Isabel Achatz, Carla Rosenberg, Dirce Maria Carraro, Ana Cristina Krepischi. Rare germline copy number variations in hereditary cutaneous melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2014-3418

Abstract 3420: TERT promoter mutations are rare in uveal melanoma

Abstract Uveal melanoma is the most frequent primary tumor of the eye. It is molecularly clearly distinct from cutaneous melanoma and shows a different pattern of driver mutations. The influence of sunlight UV-exposure on the etiology of uveal melanoma is matter of debate. The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma. We also analyzed the frequency of other recently discovered uveal melanoma specific mutations in the genes GNAQ, GNA11, BAP1, SF3B1, and EIFAX1, and we analyzed the association of these mutation with histopathological and clinical features including progression free survival. Finally, we analyzed TERT expression in these tumors. The mutation frequencies observed confirmed the prevalence of GNAQ mutations in cases with disomy of chromosome 3 that have a better prognosis whereas GNA11 was more frequent in monosomic cases. Together these two mutations account for more than 85% of the cases. BAP1 mutations are associated with chromosome 3 monosomy but not with progression free survival. SF3B1 and EIF1AX mutations occur in 10.3 and 22.5% of uveal melanomas, in disomic cases only. We detected a TERT mutation in only one case of a 57-year old white male with clinical and histo-pathological features typical for uveal melanoma. The tumor showed mutations in GNA11 and EIF1AX. No mutations were detected in GNAQ, BAP1, and SF3B1. Both copies of chromosome 3 were retained. Several tumors among which the one carrying the TERT promoter mutation showed elevated TERT expression. These data indicate that TERT mutations are rare in uveal melanoma, consistent with a reduced etiological influence of sunlight. No conclusion can be drawn on the potential influence of TERT mutations on tumor progression. Citation Format: Adriana Agnese AMARO, Marina Gualco, Maria Dono, Ulrich Pfeffer, Irena Maric, Carlo Mosci. TERT promoter mutations are rare in uveal melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3420. doi:10.1158/1538-7445.AM2014-3420

A clinicopathological review of 33 patients with vulvar melanoma identifies c-KIT as a prognostic marker

Vulvar melanoma is the second most common vulvar cancer. Patients with vulvar melanoma usually present with the disease at a late stage and have a poor prognosis. The prognostic predictors reported in the literature are not unequivocal and the role of lichen sclerosus and c-KIT mutations in the aetiology of vulvar melanoma is unclear. Breslow staging currently seems to be the most adequate predictor of prognosis. We thus performed a clinicopathological and literature review to identify suitable predictors of prognosis and survival and investigated the expression of c-KIT (by immunohistochemistry) in patients with vulvar melanoma (n=33) from the Gynaecological Cancer Centres of the Royal Hospital for Women (Sydney, Australia) and John Hunter Hospital (Newcastle, Australia). Our series of 33 patients fitted the expected clinical profile of older women: delayed presentation, high stage, limited response to treatment and poor prognosis. We identified 3 patients (9.1%) with lichen sclerosus associated with melanoma in situ, although no lichen sclerosus was found in the areas of invasive melanoma. No patient had vulvar nevi. We identified a) Breslow’s depth, b) an absence of any of the pathological risk factors, such as satellitosis, in-transit metastasis, lymphovascular space invasion (LVSI) and dermal mitosis, c) removal of inguino-femoral lymph nodes, d) lateral margin of >1 cm, and e) c-KIT expression as valuable prognostic predictors for disease-free survival. We conclude that c-KIT expression is, apart from Breslow’s depth, another valuable predictor of prognosis and survival. Lichen sclerosus may be associated with vulvar melanoma.

Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in the TERT gene promoter in a single case of uveal melanoma

Background:Uveal melanoma is the most frequent primary tumour of the eye. It is molecularly clearly distinct from cutaneous melanoma and shows a different pattern of driver mutations. The influence of sunlight ultraviolet (UV) exposure on the aetiology of uveal melanoma is a matter of debate. The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV-induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma.Methods:We analysed 50 cases of uveal melanoma obtained from enucleation surgery for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT, measured gene expression using microarrays and analysed gene copy numbers by SNP arrays.Results:We detected a TERT mutation in only one case of a 57-year-old white male patient with clinical and histopathological features typical for uveal melanoma. The tumour showed mutations in GNA11 and EIF1AX that are typical for uveal melanoma and absent from cutaneous melanoma. No mutations were detected in GNAQ, BAP1 and SF3B1 that are frequently mutated in uveal melanoma. Both copies of chromosome 3 were retained. Several tumours among which the one carrying the TERT promoter mutation showed elevated TERT expression. Consistent with previous reports, GNAQ is inversely associated with chromosome 3 monosomy and metastasis. BAP1 mutations are significantly associated with chromosome 3 monosomy but not with relapse.Conclusion:These data indicate that TERT mutations are rare in uveal melanoma. No conclusion can be drawn on their potential influence on tumour progression.

Activity of cathepsin D and α1-antitrypsin in blood of men with malignant melanoma.

IntroductionThe aetiopathology of melanoma is (like in other cancers) a result of environmental factors and genetic predispositions. One of the most important environmental factors which has an influence on melanoma aetiology is exposure to UV radiation.AimTo estimate the activity of selected parameters in melanoma diagnosis.Material and methodsIn serum of 25 men with melanoma, activity of cathepsin D and α1-antitrypsin (important inhibitors of protease) was estimated. It was a heterogeneous group, because some men were classified according to Clark’s classification, and other men were classified by Breslow’s classification. Three months after resection of the lesion, only 13 men came back for the next tests.ResultsActivity of α1-antitrypsin in patients before and after removing the affected tissue was similar and related to the control value (0.78 mg of trypsin). Medium activity of cathepsin D in the control group was about 11.88 nM. Activity in patients before surgery was lower: 8.94 nM. After removing the tumour, this activity was 9.31 nM.ConclusionsIt can be supposed that the proteolytic-antiproteolytic balance was disturbed in persons with melanoma, because the activity of cathepsin D in serum of these people was lower than in healthy people, but the activity of α1-antitrypsin was not changed.

Melanocytes and Melanoma Etiology

Melanocytes are pigment-producing cells originated from the neural crest. Epidermal melanocytes contribute to photoprotection and thermoregulation by packaging melanin pigment intomelanosomes and sending them to keratinocytes. There are still many gaps in the understanding of early events of melanocyte differentiation and advanced melanoma regarding genetic and molecular processes. In this review, the authors present a summary of the main aspects of the melanocyte biology and its relation with the melanoma etiology, which are of major importance for guiding novel therapies development and to well understand this disease.

Aetiology, clinical presentation and current treatment options of equine malignant melanoma – a review of the literature

Aetiology, clinical presentation and current treatment options of equine malignant melanoma – a review of the literature

Acral Melanoma

Compared with the US melanoma incidence rate of 21.1 per 100 000 population from2006 through 2010, a low incidence rateofmelanoma(≤1/100 000)wasreported inEastAsiancountries includingTaiwan,China, Japan,Korea,HongKong,and Singapore. The most common subtype in these countries was acral lentiginous melanoma, which comprised approximately50%to58%ofcutaneousmelanoma.1-6 Incontrast, acral lentiginousmelanoma represented 2% to 3%of allmelanoma among Western populations. Cutaneous acral lentiginousmelanomausually presents in areaswith little to no sun exposure (such as palms, soles, and nail apparatus). Another sun exposure–independent melanoma is mucosal melanoma, which comprised 22% of melanoma in China in 2011.3 ComparedwithWestern countries, where superficial spreadingmelanomacomprisedapproximately 50%to70%,only approximately 5% to 37% of cutaneous melanoma was superficial spreading melanoma in East Asia, where sun-seeking behavior is not as popular as in Western countries. In Asian countries, cutaneous melanoma tends to be diagnosed at an advanced stageand results in low5-year survival rates (Table). UV light exposure has been implicated as a major etiology in the development of melanoma. The defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. UV-induced DNA photoproducts are able to cause specific mutations in genes susceptible to developing skin cancers. Recent molecular genetic investigations have revealed thatmelanomas fromsun-exposedareas showedfrequentmutations in either theBRAF orNRAS gene. In contrast,BRAF or NRASmutations were infrequent in melanomas arising from non–sun-exposedareas, suchas acral skin,nail apparatus, and mucosa. Instead, these types of melanomas showed a higher degreeof chromosomal aberrations; specifically, genomic amplifications involving small portionsof chromosomearms.7 In acral melanoma, the most frequently amplified region was chromosome 11q13, which contains the CCND1 gene. This region has not been well studied in Asian melanoma. The etiology of acral melanoma in Asia remains to be determined. Inanetiological studyofacralmelanomas fromAustralia, an increased risk was associated with penetrating injuryof the feet orhands (relative risk [RR], 5.0) andwithheavy exposure to agricultural chemicals (RR, 3.6).8 These risk factors could be also true in other Asian countries. In this issue, Jung and coauthors4 reported the characteristics of 177 acral melanomas in Korea. This is an important article that explores thepossiblecausesofacralmelanomainEastAsia.Based on theobservational study, theauthorsdemonstratedahigher incidenceofacralmelanomaatmorephysicallypressuredsites (such as the center area of the heels and inner forefoot) than non–physically pressured areas in the acral skin. The authors also observed that acral melanoma tended to spread along naturally occurring creases of the skin. They concluded that chronic physical pressure could influence the incidence and spreading pattern of acral melanoma. Among the 52 patients that provided their trauma history, 15 (29%) patients had evident histories of previous trauma on their sites ofmelanoma. Thisobservationseemstobeconsistentwith theworkofGreen andcoauthors8 suggesting traumaasa risk factorof acralmelanoma. It should be noted that the study by Jung et al4 is observational. Further research with a case-control study is needed to determine the extent and impact of trauma on the developmentofacralmelanoma.Nonetheless, thestudysheds light on the possible etiology of acral melanoma in East Asia. Related article page 1281

CXCR4 pathway associated with family history of melanoma

Genetic predisposition plays a major role in the etiology of melanoma, but known genetic markers only account for a limited fraction of family-history-associated melanoma cases. Expression microarrays have offered the opportunity to identify further genomic profiles correlated with family history of melanoma. We aimed to distinguish mRNA expression signatures between melanoma cases with and without a family history of melanoma. Based on the Nurses' Health Study, family history was defined as having one or more first-degree family members diagnosed with melanoma. Melanoma diagnosis was confirmed by reviewing pathology reports, and tumor blocks were collected by mail from across the USA. Genomic interrogation was accomplished through evaluating expression profiling of formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, on either a 6K or whole-genome (24K) Illumina gene chip. Gene set enrichment analysis was performed for each batch to determine the differentially enriched pathways and key contributing genes. The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF mutation, or Breslow thickness of the primary melanoma cases. We found that the CXCR4 pathway might constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives.

Implication of ultraviolet light in the etiology of uveal melanoma: A review

Uveal melanoma is the most frequent intraocular cancer and the second most common form of melanoma. It metastasizes in half of the patients and the prognostic is poor. Although ultraviolet (UV) radiation is a proven risk factor for skin melanoma, the role of UV light in the etiology of uveal melanoma is still contradictory. We have compared epidemiological and genetic evidences of the potential role of UV radiation in uveal melanoma with data on cutaneous melanoma. Even though frequently mutated genes in skin melanoma (e.g. BRAF) differ from those found in uveal melanoma (i.e. GNAQ, GNA11), their mutation pattern bears strong similarities. Furthermore, we provide new results showing that RAC1, a gene recently found harboring UV-hallmark mutation in skin melanoma, is also mutated in uveal melanoma. This article aims to review the work done in the last decades to understand the etiology of uveal melanoma and discuss new avenues, which shed some light on the potential role of UV exposure in uveal melanoma.

Melanoma genotypes and phenotypes get personal

Traditionally, the diagnosis of metastatic melanoma was terminal to most patients. However, the advancements towards understanding the fundamental etiology, pathophysiology, and treatment have raised melanoma to the forefront of contemporary medicine. Indeed, the evidence of durable remissions are being heard ever more frequently in clinics around the globe. Despite having more gene mutations per cell than any other type of cancer, investigators are overcoming complex genomic landscapes, signaling pathways, and immune checkpoints by generating novel technological methods and clinical protocols with breath-taking speed. Significant progress in deciphering molecular genetics, epigenetics, kinase-driven networks, metabolomics, and immune-enhancing pathways to achieve personalized and positive outcomes has truly provided new hope for melanoma patients. However, obstacles requiring breakthroughs include understanding the influence of sunlight exposure on melanoma etiology, and overcoming all too frequently acquired drug resistance, complicating targeted therapy. Pathologists continue to have critically important roles in advancing the field, particularly in the area of transitioning from microscope-based diagnostic reports to pharmacogenomics through molecularly informed tumor boards. Although melanoma is no longer considered just ‘one disease’, pathologists will continue this rapidly progressing and exciting journey to identify tumor subtypes, to utilize tumorgraft or so-called patient-derived xenograft (PDX) models, and to develop companion diagnostics to keep pace with the bewildering breakthroughs occurring on a regular basis. Exactly which combination of drugs will ultimately be required to eradicate melanoma cells remains to be determined. However, it is clear that pathologists who are as dedicated to melanoma as the pioneering pathologist Dr Sidney Farber was committed to childhood cancers, will be required as the battle against melanoma continues. In this review, we describe what sets melanoma apart from other tumors, and demonstrate how lessons learned in the melanoma clinic are being transferred to many other types of aggressive neoplasms.