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Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma in adults. However, it is rare in middle childhood. Such cases usually present with hypopigmented patches that may mimic common childhood dermatoses, thereby causing a delay in the diagnosis. Sezary syndrome is a rare and aggressive leukaemic variant of cutaneous lymphoma. We report a patient in middle childhood who presented with recurring non-specific folliculotropic manifestations. The final diagnosis of MF was arrived at after excluding all other possible dermatoses. Within a few months of skin manifestations, our index child was found to have blood involvement with similar clonal T-lymphoid cells. Such rapid development of Sezary syndrome within months of cutaneous presentation has never been described. There are no established treatment guidelines for the same in paediatric population. The patient underwent a matched sibling allogeneic transplant after a course of topical steroids and skin electron beam therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with α-galactosylceramide (α-GalCer), an agonist for type 1 Natural Killer T (NKT) cells., Objective: To assess whether inclusion of α-GalCer in autologous NY-ESO-1 long peptide-pulsed DC vaccines (DCV + α-GalCer) improves T cell responses when compared to peptide-pulsed DC vaccines without α-GalCer (DCV)., Design, Setting and Participants: Single-centre blinded randomised controlled trial in patients ≥ 18 years old with histologically confirmed, fully resected stage II-IV malignant cutaneous melanoma, conducted between July 2015 and June 2018 at the Wellington Blood and Cancer Centre of the Capital and Coast District Health Board., Interventions: Stage I. Patients were randomised to two cycles of DCV or DCV + α-GalCer (intravenous dose of 10 × 10 6 cells, interval of 28 days). Stage II. Patients assigned to DCV + α-GalCer were randomised to two further cycles of DCV + α-GalCer or observation, while patients initially assigned to DCV crossed over to two cycles of DCV + α-GalCer., Outcome Measures: Primary: Area under the curve (AUC) of mean NY-ESO-1-specific T cell count detected by ex vivo IFN-γ ELISpot in pre- and post-treatment blood samples, compared between treatment arms at Stage I. Secondary: Proportion of responders in each arm at Stage I; NKT cell count in each arm at Stage I; serum cytokine levels at Stage I; adverse events Stage I; T cell count for DCV + α-GalCer versus observation at Stage II, T cell count before versus after cross-over., Results: Thirty-eight patients gave written informed consent; 5 were excluded before randomisation due to progressive disease or incomplete leukapheresis, 17 were assigned to DCV, and 16 to DCV + α-GalCer. The vaccines were well tolerated and associated with increases in mean total T cell count, predominantly CD4 + T cells, but the difference between the treatment arms was not statistically significant (difference - 6.85, 95% confidence interval, - 21.65 to 7.92; P = 0.36). No significant improvements in T cell response were associated with DCV + α-GalCer with increased dosing, or in the cross-over. However, the NKT cell response to α-GalCer-loaded vaccines was limited compared to previous studies, with mean circulating NKT cell levels not significantly increased in the DCV + α-GalCer arm and no significant differences in cytokine response between the treatment arms., Conclusions: A high population coverage of NY-ESO-1-specific T cell responses was achieved with a good safety profile, but we failed to demonstrate that loading with α-GalCer provided an additional advantage to the T cell response with this cellular vaccine design., Clinical Trial Registration: ACTRN12612001101875. Funded by the Health Research Council of New Zealand., (© 2023. The Author(s).)

Background: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM) and the potential to stratify patients at high risk of death has not been comprehensively studied., Objective: To investigate the epidemiologic, clinical, and mutational profile of primary cutaneous melanomas with a thickness ≥ 1 mm, stratified by rate of growth., Methods: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin-embedded primary melanoma samples. Comparison of FGMM (rate of growth > 0.5 mm/month) and nonFGMM (rate of growth ≤ 0.5 mm/month)., Results: Two hundred patients were enrolled, among wom 70 had FGMM. The relapse-free survival was lower in the FGMM group (P = .014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than nonFGMM (P = .033). Ulceration (P = .032), thickness (P = .006), lower sun exposure (P = .049), and fibroblast growth factor receptor 2 (FGFR2) mutations (P = .037) were significantly associated with fast growth., Limitations: Single-center study, cohort size, potential memory bias, number of investigated genes., Conclusion: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness, and FGFR2 mutations are associated with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM, which are probably good candidates for adjuvant therapies., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Acral location of melanomas is associated with poor survival. It can be due, at least in part, to the fact that acral lentiginous melanoma, a distinct melanoma subtype, has a particular biological profile and a bad clinical behavior. However, since almost 50% of acral melanomas are not of acral lentiginous melanoma subtype, the worse clinical behavior could also be attributable to the intrinsic characteristics of the location., Objective: This study aimed to investigate if melanomas of the lower limb excluding acral lentiginous melanoma differ by location., Methods: This retrospective, observational study recruited patients from an oncology referral center in Spain. We included 285 patients with superficial spreading and nodular melanomas of the lower limb. We compare melanomas by site, clinical and pathological characteristics, and the differences by location of disease-free and melanoma-specific survival by the Kaplan-Meier method and Cox proportional hazard method., Results: Patients with melanomas on the foot, compared to those on the rest of the limb, were older and reported having suffered less sunburns; the melanoma more frequently appeared in areas that had been rarely sun exposed, were more frequently of nodular type, presented thicker tumors, with more ulceration, less regression, and more advanced stage of the disease. Foot location increased the risk of relapse and decreased melanoma-specific survival., Conclusion: Melanoma development in foot is less related to sun exposure and is associated with pathological features that can account for the worse prognosis and poorer survival., (© 2022 S. Karger AG, Basel.)

Background: KIT mutations are primarily associated with acral and mucosal melanoma, and have been reported to show higher prevalence in chronic sun-damaged (CSD) than non-CSD melanomas., Objectives: To investigate the prevalence of KIT mutations in melanoma according to subtype, and determine the clinical role of such mutations., Materials & Methods: We present results from a study of a Spanish population of 492 melanomas, classified according to the latest World Health Organization (WHO) guidelines. We analysed the mutational status of KIT and correlated with different clinical variables related to sun exposure and family history., Results: KIT mutations were significantly more frequent in acral (3/36; 8.3%) and mucosal (4/8; 50%) melanomas than non-acral cutaneous melanomas. No significant difference was observed in KIT mutational status between CSD and non-CSD melanomas., Conclusion: Our results suggest that KIT mutations in melanoma tumours are unrelated to the development of nevi or chronic sun damage, but their presence is associated with aggressive melanomas which show ulceration, vascular invasiveness, and increased Breslow thickness. These findings are consistent with those reported by The Cancer Genome Atlas network.

Most relapses in melanoma patients occur during the first five years after diagnosis. Identifying characteristics associated with recurrence after this period could help delineate guidelines, specifically for follow-up protocols. Objectives: The aim of this study was to identify the prognostic factors for relapse and death caused by melanoma in patients who have been disease-free for five years. We designed a longitudinal retrospective cohort to study Stage I/II cutaneous melanoma patients who have been free of disease for more than five years (late relapse cohort). Prognostic factors for disease-free and melanoma-specific survival were evaluated using the Kaplan-Meier method and Cox regression models. A series of 746 patients who had Stage I-II cutaneous melanoma and were free of disease for five years was selected. After a median follow-up of 64 months (124 months since melanoma diagnosis), 51 (6.8%) patients relapsed and 18 (2.4%) died from melanoma. Acral location and presence of ulceration, as well as intermediate growth rate (0.11-0.50 mm/month), were significantly associated with relapse or death due to melanoma. The initial recurrence site was associated with distant metastasis in 48% of the cases. In this study, we have identified melanoma characteristics in patients who have been disease-free for five years that may allow us to establish groups at increased risk of relapse or death due to melanoma, which could be helpful for melanoma management.

Aim: To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Materials & methods: Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions. Results: Methylation levels were lower in melanomas than in nevi. HERV-K and LINE-1 methylation were decreased in melanoma patients with clinical parameters associated with adverse prognosis, while they were independent of age and gender. Hypomethylation of HERV-K (but not LINE-1) was an independent predictor of reduced disease-free survival. Conclusion : HERV-K hypomethylation can be a potential independent biomarker of melanoma recurrence.

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10 -8 ) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Telomere length per se a heritable trait has been reported to be associated with different diseases including cancers. In this study, based on arsenic-exposed 528 cases with basal cell carcinoma (BCC) of skin and 533 healthy controls, we investigated effect of telomere length, measured by real-time PCR, on the disease risk. We observed a statistically significant association between decreased telomere length and increased BCC risk [odds ratio (OR) = 5.92, 95% confidence interval (CI) = 3.92 to 9.01, P < 0.0001]. Due to confounder effect of arsenic exposure, in a two-sample Mendelian randomization (MR), telomere length associated single-nucleotide polymorphisms as instrument variables violated valid assumptions; however, one-sample MR adjusted for arsenic exposure indicated an increased risk of BCC with short telomeres. The interaction between arsenic exposure and telomere length on BCC risk was statistically significant (P = 0.02). Within each tertile based on arsenic exposure, the individuals with shorter telomeres were at an increased risk of BCC, with highest risk being in the highest exposed group (OR = 16.13, 95% CI = 6.71 to 40.00, P < 0.0001), followed by those in medium exposure group and low exposure group. The combined effect of highest arsenic exposure and shortest telomeres on BCC risk (OR = 10.56, 95% CI = 5.14 to 21.70) showed a statistically significant departure from additivity (interaction contrast ratio 6.56, P = 0.03). Our results show that in the presence of arsenic exposure, decreased telomere length predisposes individuals to increased risk of BCC, with the effect being synergistic in individuals with highest arsenic exposure and shortest telomeres., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: The lymphatic and the hematogenous pathways have been proposed for disease progression in cutaneous melanoma, but association with recurrence has not been studied separately to date., Objective: To identify the risk factors associated with lymphatic and hematogenous metastasis., Design, Setting, and Participants: This retrospective cohort study included 1177 patients with malignant melanoma treated at Instituto Valenciano de Oncología, València, Spain. Data were retrieved from the melanoma database from January 1, 2000, through December 31, 2015, and analyzed from June 1 to 30, 2018., Exposure: Malignant melanoma at stages I to II., Main Outcomes and Measures: Analyses of survival free of lymphatic and hematogenous metastasis were performed using Kaplan-Meier curves and Cox proportional hazards regression., Results: For the 1177 patients included in the study analysis (51.1% women; median age at diagnosis, 55 years [interquartile range, 42-68 years), median follow-up was 75 months (interquartile range, 33-121 months); 108 (9.2%) developed lymphatic metastasis, and 108 (9.2%) developed hematogenous metastasis. In the multivariate analysis, being older than 55 years (hazard ratio [HR], 1.9; 95% CI, 1.2-3.1), tumor in the head/neck (HR, 1.7; 95% CI, 1.0-2.9) and acral locations (HR, 2.4; 95% CI, 1.3-4.5), greater Breslow thickness (HR for >4.00 mm, 5.4; 95% CI, 2.4-12.4), and presence of vascular invasion (HR, 3.2; 95% CI, 0.9-10.6) were associated with lymphatic spreading. Hematogenous metastasis was associated with greater Breslow thickness (HR for >4.00 mm, 10.4; 95% CI, 3.6-29.7), the absence of regression (HR, 0.1; 95% CI, 0.0-1.0), TERT promoter mutations (HR, 2.9; 95% CI, 1.5-5.7), and BRAF mutations (HR, 1.9; 95% CI, 1.1-3.6)., Conclusions and Relevance: Risk factors associated with lymphatic and hematogenous metastasis differ. Follow-up and adjuvant treatment strategies may therefore need to be adapted to individual clinical, histopathologic, and molecular characteristics.

Telomere repeats at chromosomal ends, critical to genomic integrity, undergo age-dependent attrition. Telomere length, a polygenic trait, has been associated with risk of several disorders including cancers. In contrast to association of long telomeres with increased risk of several cancers, including melanoma, emerging reports suggest that short telomeres predict poor survival in patients with different cancers. In this study based on 1019 stage I and II cutaneous melanoma patients, we show an association between the patients with short telomeres and poor melanoma-specific survival (HR 2.05, 95% CI 1.33-3.16) compared to patients with long telomeres. Due to inverse correlation between age and telomere length (r -0.19, P < 0.0001), we stratified the patients into quantiles based on age at diagnosis and also carried out age-matched analysis. The effect of short telomeres on survival was determined by using multivariate Cox regression that included composite genetic risk score computed from genotyping of the patients for telomere-length associated polymorphisms. The effect of decreased telomere length on poor melanoma-specific survival was particularly strong in patients within the age quantile below 30 years (HR 3.82, 95% CI 1.10-13.30) and between 30-40 years (HR 2.69, 95% CI 1.03-7.03). Our study shows that in contrast to increased melanoma risk associated with increased telomere length, decreased telomere length predicts poor survival in melanoma subgroups.

The aim of this case-case study was to determine the differences between dysplastic and common naevus-associated melanomas (NAM) and de novo melanomas. A total of 1,021 prospectively collected patients with invasive cutaneous melanoma from an oncology referral centre were included in the study. Of these, 75.51% had de novo melanomas, 12.93% dysplastic NAM, and 11.56% common NAM. Dysplastic NAM, compared with de novo melanomas, were associated with intermittently photo-exposed sites, atypical melanocytic naevi, decreased tumour thickness, and presence of MC1R non-synonymous variants. Common NAM were more frequent on the trunk and of superficial spreading type. Comparison of dysplastic with common NAM showed significant difference only with regard to mitoses. Both subtypes of NAM shared less aggressive traits than de novo melanomas, albeit with no significant differences in survival after multivariate adjustment. In conclusion, NAM present with less aggressive traits, mostly due to a greater awareness among patients of changing moles than due to their intrinsic biological characteristics.

Melanoma results from a complex interplay between environmental factors and individual genetic susceptibility. Familial melanoma is attributable to predisposition genes with variable penetrance. The aim of this study was to identify differences between familial melanoma and sporadic cases in our population, based on the presence of CDKN2A mutations and MC1R variants. Comparing 107 patients with familial melanoma from 87 families (17% CDKN2A mutated) with 1,390 cases of sporadic melanomas, the former were younger and exhibited an increased prevalence of atypical naevi and squamous cell carcinoma (SCC). CDKN2A mutation carriers presented more atypical naevi, multiple melanomas, and basal cell carcinoma, while non-carriers were more likely to have light-coloured hair, atypical naevi, and SCC. MC1R variants decreased the age at diagnosis in all groups and were associated with an increased prevalence of SCC, especially in patients with familial melanoma without CDKN2A mutations. These characteristics may help to establish prevention measures targeting patients with familial melanoma in the Mediterranean area.

Background: Melanoma survivors are at an increased risk of developing other malignancies, including keratinocyte skin cancer (KSC). While it is known that many risk factors for melanoma also impact risk of KSC in the general population, no previous study has investigated risk factors for KSC development in melanoma patients., Objective: We assessed associations of personal and clinical characteristics, including skin phenotype and variations in the melanocortin 1 receptor (MC1R) gene, with KSC risk in melanoma patients., Patients and Methods: We used prospective follow-up information on 1200 patients treated for melanoma at the Instituto Valenciano de Oncología, Spain, between 2000 and 2011. We computed hazard ratios and 95% confidence intervals (CIs) for the association of clinical, personal and genetic characteristics with risk of KSC, squamous cell carcinoma (SCC), or basal cell carcinoma (BCC) from Cox proportional hazard models. Five-year cumulative incidence based on competing risk models of SCC, BCC or KSC overall was computed using multivariate subdistribution hazard models. To assess predictive performance of the models, we computed areas under the receiver-operating characteristic curves (AUCs, discriminatory power) using cross-validation., Results: Median follow-up was 57.2 months; a KSC was detected in 163 patients (13.6%). In multivariable Cox models, age, sex, sunburns, chronic sun exposure, past personal history of non-melanoma skin cancer or other non-cutaneous neoplasia, and the MC1R variants p.D294H and p.R163Q were significantly associated with KSC risk. A cumulative incidence model including age, sex, personal history of KSC, and of other non-cutaneous neoplasia had an AUC of 0.76 (95% CI: 0.71-0.80). When p.D294H and p.R163Q variants were added to the model, the AUC increased to 0.81 (95% CI: 0.77-0.84) (p-value for difference <0.0001)., Conclusions: In addition to age, sex, skin characteristics, and sun exposure, p.R163Q and p.D294H MC1R variants significantly increased KSC risk among melanoma patients. Our findings may help identify patients who could benefit most from preventive measures., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Melanoma incidence is higher in patients affected by Parkinson's disease (PD) and vice versa, but the genetic link shared by both diseases is unknown. As PARK2 is both a tumor suppressor gene and frequently mutated in young onset PD, we evaluated the role of PARK2 in melanoma predisposition and progression., Methods: An in-depth PARK2 gene dosage analysis and sequencing was performed on 512 French case patients and 562 healthy control patients, as well as sporadic tumors and melanoma cell lines. The frequency of genetic alterations was compared between case patients and control patients using two-sided Fisher's exact tests and odds ratio (OR) calculations. We used western blotting to determine PARKIN expression in melanocytes and melanoma cell lines and transfection followed by clonogenic assays to evaluate the effect of PARKIN expression on cellular proliferation. All statistical tests were two-sided., Results: Germline PARK2 mutations (including copy number variations, splicing, and putative deleterious missense mutations) were present in 25 case patients but only four control patients (OR = 3.95, 95% confidence interval = 1.34 to 15.75). Copy number variations (CNVs) and loss of heterozygosity were present in 60% and 74%, respectively, of primary tumors. PARKIN protein was expressed in melanocytes but not in most melanoma cell lines, and its expression decreased following melanocyte transformation by oncogenic NRAS. Re-expression of PARKIN in melanoma cell lines resulted in a drastic reduction of cell proliferation and inhibition of PARKIN in melanocytes stimulated their proliferation., Conclusion: Our results show an important role for PARK2 as a tumor suppressor both in melanoma predisposition and progression, which could explain the epidemiological association of these diseases., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Recent reports suggested frequent occurrence of cancer associated somatic mutations within regulatory elements of the genome. Based on initial exome sequencing of 21 melanomas, we report frequent somatic mutations in skin cancers in a bidirectional promoter of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes. The UV-signature mutations occurred at sites adjacent and within a binding motif for E-twenty six/ternary complex factors (Ets/TCF), at -8 and -9 bp from DPH3 transcription start site. Follow up screening of 586 different skin lesions showed that the DPH3 promoter mutations were present in melanocytic nevi (2/114; 2%), melanoma (30/304; 10%), basal cell carcinoma of skin (BCC; 57/137; 42%) and squamous cell carcinoma of skin (SCC; 12/31; 39%). Reporter assays carried out in one melanoma cell line for DPH3 and OXNAD1 orientations showed statistically significant increased promoter activity due to -8/-9CC > TT tandem mutations; although, no effect of the mutations on DPH3 and OXNAD1 transcription in tumors was observed. The results from this study show occurrence of frequent somatic non-coding mutations adjacent to a pre-existing binding site for Ets transcription factors within the directional promoter of DPH3 and OXNAD1 genes in three major skin cancers. The detected mutations displayed typical UV signature; however, the functionality of the mutations remains to be determined.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Background: Melanoma is considered a heterogeneous tumor with genetic and environmental factors involved in its pathogenesis. The impact of these factors varies depending on age., Objective: The aim of this study was to characterize the epidemiological, phenotypic, and histological features of patients with melanoma according to three age groups: ≤40, 41-65, and >65 years., Methods: A total of 1122 consecutive patients with invasive melanoma definitively treated in our institution since January 2000 were selected from our melanoma database. Epidemiological, phenotypic, and histological data were retrieved and analyzed as a function of age., Results: Female patients predominated in the younger age group. The location of cutaneous malignant melanoma differed with age. In the younger and middle age groups, tumors presented mainly on the trunk, while in the older group they were mainly found on the head/neck. Signs of actinic damage such as actinic keratoses, solar lentigines, or other skin tumors increased with age, while genetic factors such as family history of melanoma or a high number of common melanocytic nevi were more frequent in the younger group., Conclusion: Our results suggest that melanoma development in younger patients is the result of genetic factors, particularly related to multiple nevi, whereas in older patients environmental factors such as severe chronic sun exposure play a major role., (© 2015 The International Society of Dermatology.)

In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.

The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wild-type subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fair-skinned subjects., (© 2014 UICC.)

X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3) polymorphisms are relatively frequent in Caucasian populations and may have implications in skin cancer modulation. A few studies have evaluated their association with non-melanoma skin cancer (NMSC), but the results are inconsistent. In the current study, we aim to assess the impact of XRCC1 R399Q and XRCC3 T241M polymorphisms on the risk of NMSC associated with sunlight and arsenic exposure. Study participants consist of 618 new cases of NMSC and 527 hospital-based controls frequency matched on age, sex, and county of residence from Hungary, Romania, and Slovakia. Adjusted effects are estimated using multivariable logistic regression. The results indicate an increased risk of squamous cell carcinoma (SCC) for the homozygous variant genotype of XRCC1 R399Q (OR 2.53, 95% CI 1.14-5.65) and a protective effect against basal cell carcinoma (BCC) for the homozygous variant genotype of XRCC3 T241M (OR 0.61, 95% CI 0.41-0.92), compared with the respective homozygous common genotypes. Significant interactions are detected between XRCC3 T241M and sunlight exposure at work, and between XRCC3 T241M and exposure to arsenic in drinking water (p-value for interaction <0.10). In conclusion, the current study demonstrates that polymorphisms in XRCC genes may modify the associations between skin cancer risk and exposure to sunlight or arsenic. Given the high prevalence of genetic polymorphisms modifying the association between exposure to environmental carcinogens and NMSC, these results are of substantial relevance to public health., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We previously reported a disease segregating causal germline mutation in a melanoma family and recurrent somatic mutations in metastasized tumours from unrelated patients in the core promoter region of the telomerase reverse transcriptase (TERT) gene. Here we show that the TERT promoter mutations, besides causing an increased gene expression, associate with increased patient age, increased Breslow thickness and tumour ulceration in 287 primary melanomas. The mutations are more frequent at both intermittently and chronically sun-exposed sites than non-exposed sites and tend to co-occur with BRAF and CDKN2A alterations. The association with parameters generally connected with poor outcome, coupled with high recurrence and mechanistic relevance, raises the possibility of the eventual use of TERT promoter mutations in the disease management.

Occupational studies show a high risk of lung cancer related to arsenic exposure by inhalation; however, only a few studies, and with conflicting results, previously examined a potential link between arsenic exposure at work and skin cancer. The aim of this study is to assess airborne arsenic exposures at the workplace and to quantify associations with nonmelanoma skin cancer (NMSC). The study sample consists of 618 incident cases of NMSC and 527 hospital-based controls aged 30-79 years from Hungary, Romania and Slovakia. Exposures were evaluated by local experts using occupational histories. Information on host factors and other exposures was collected and used to adjust the associations of interest using multivariable logistic regression. The lifetime prevalence of exposure to work-related arsenic is 23.9% for cases and 15.5% for controls. No significant association between arsenic exposure in the workplace and NMSC was detected, although an increased adjusted odd ratio was observed for participants with higher cumulative lifetime workplace exposure to arsenic in dust and fumes compared to referents [odds ratios (OR) = 1.94, 95% confidence interval (CI) = 0.76-4.95]. There is evidence for modification of the workplace arsenic-NMSC association by work-related sunlight exposure in women, with a markedly increased adjusted OR in the presence of workplace sunlight exposure (OR = 10.22, 95% CI = 2.48-42.07). Workplace coexposure to arsenic and sunlight may thus pose an increased risk of NMSC., (© 2013 UICC.)

Background: The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS)., Methods: In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region., Results: All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3' UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A-allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54)., Conclusions: Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes.

Background: Studies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation., Objectives: We investigated potential associations between natural and artificial UV radiation exposure at work with NMSC in a case-control study conducted in Hungary, Romania, and Slovakia., Methods: Occupational exposures were classified by expert assessment for 527 controls and 618 NMSC cases (515 basal cell carcinoma, BCC). Covariate information was collected via interview and multiple logistic regression models were used to assess associations between UV exposure and NMSC., Results: Lifetime prevalence of occupational exposure in the participants was 13% for natural UV radiation and 7% for artificial UV radiation. Significant negative associations between occupational exposure to natural UV radiation and NMSC were detected for all who had ever been exposed (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.27-0.80); similar results were detected using a semi-quantitative metric of cumulative exposure. The effects were modified by skin complexion, with significantly decreased risks of BCC among participants with light skin complexion. No associations were observed in relation to occupational artificial UV radiation exposure., Conclusions: The protective effect of occupational exposure to natural UV radiation was unexpected, but limited to light-skinned people, suggesting adequate sun-protection behaviors. Further investigations focusing on variations in the individual genetic susceptibility and potential interactions with environmental and other relevant factors are planned.

Cutaneous melanoma occurs in both familial and sporadic forms. We investigated a melanoma-prone family through linkage analysis and high-throughput sequencing and identified a disease-segregating germline mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase. The mutation creates a new binding motif for Ets transcription factors and ternary complex factors (TCFs) near the transcription start and, in reporter gene assays, caused up to twofold increase in transcription. We then screened the TERT promoter in sporadic melanoma and observed recurrent ultraviolet signature somatic mutations in 125 of 168 (74%) of human cell lines derived from metastatic melanomas, 45 of 53 corresponding metastatic tumor tissues (85%), and 25 of 77 (33%) primary melanomas. The majority of those mutations occurred at two positions in the TERT promoter and also generated binding motifs for Ets/TCF transcription factors.

Background: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia., Design and Methods: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling., Discussion: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields.

A divergent pathway model to cutaneous melanoma is commonly accepted: sun sensitivity/chronic sun exposure and melanocytic instability. Although this dual model explains the development of most melanomas, clinical experience suggests other possible routes. The aim of this study was to explore the characteristics of patients who do not fit with these two pathways. We selected 818 patients with nonacral cutaneous melanoma and defined three groups: nevus-prone individuals, sun-sensitive individuals, and non-nevus-prone and non-sun-sensitive individuals. This group included patients without identifiable melanoma risk factors and comprised 52 patients (5.5% of the overall nonacral melanoma population). These patients were more frequently women, were more likely to present melanoma at a very young age (13.5% before 25 years), to have less frequent personal history of melanoma and remnants of pre-existing nevi, and to present tumors on the trunk and legs. We have identified a group of patients with fewer risk factors for melanoma that needs further studies to increase our understanding of melanoma development.

Integrins are transmembrane adhesion molecules that mediate cell-cell and cell-extracellular matrix attachment. Integrins regulate cell growth, proliferation, migration and apoptosis and as a consequence, can have a potential role in tumour progression and metastasis. In this study, we investigated 19 non-synonymous variants in the coding region of the human integrin genes representing 3 beta subunits and 13 alpha subunits, for their potential role in melanoma susceptibility and survival. The variants were selected on the basis of probable functional relevance and theoretical predictions. Our data showed that no genetic variant was significantly associated with survival. However, the variants in ITGA10 and ITGA6 genes showed association with decreased risk, and variants in ITGA2, ITGAE and ITGAM were associated with increased risk of melanoma. The haplotype analysis revealed association of CA haplotype of ITGAE and TAC haplotype of ITGAX with the risk modulation. A prediction analysis of functional effect, homology modelling and multiple sequence alignments of integrin sequences from different species supported our data for linkage of variants in the ITGA2 and ITGAE genes with susceptibility. The amino acid changes in each of these integrin proteins could affect intramolecularly and/or the interaction of the heterodimers. Our experimental data indicated a possible role for some of the variant alleles and/or haplotypes of the integrin genes in melanoma susceptibility, which is augmented by the theoretical analysis performed.

Background: Inorganic arsenic (iAs) is a potent carcinogen, but there is a lack of information about cancer risk for concentrations < 100 μg/L in drinking water., Objectives: We aimed to quantify skin cancer relative risks in relation to iAs exposure < 100 μg/L and the modifying effects of iAs metabolism., Methods: The Arsenic Health Risk Assessment and Molecular Epidemiology (ASHRAM) study, a case-control study, was conducted in areas of Hungary, Romania, and Slovakia with reported presence of iAs in groundwater. Consecutively diagnosed cases of basal cell carcinoma (BCC) of the skin were histologically confirmed; controls were general surgery, orthopedic, and trauma patients who were frequency matched to cases by age, sex, and area of residence. Exposure indices were constructed based on information on iAs intake over the lifetime of participants. iAs metabolism status was classified based on urinary concentrations of methylarsonic acid (MA) and dimethylarsinic acid (DMA). Associations were estimated by multivariable logistic regression., Results: A total of 529 cases with BCC and 540 controls were recruited for the study. BCC was positively associated with three indices of iAs exposure: peak daily iAs dose rate, cumulative iAs dose, and lifetime average water iAs concentration. The adjusted odds ratio per 10-μg/L increase in average lifetime water iAs concentration was 1.18 (95% confidence interval: 1.08, 1.28). The estimated effect of iAs on cancer was stronger in participants with urinary markers indicating incomplete metabolism of iAs: higher percentage of MA in urine or a lower percentage of DMA., Conclusion: We found a positive association between BCC and exposure to iAs through drinking water with concentrations < 100 μg/L.

Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46-0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65-0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67-1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients., (© 2012 John Wiley & Sons A/S.)

Basal cell carcinoma (BCC) of the skin is the most common neoplasm among the Caucasian population of the Western world. Inflammation may result in oxidative stress and contribute to promotion and progression of tumors, including BCC. The role of cytokines, which are inflammatory modulators, in the biology of tumors has been extensively studied and it is well known that they are aberrantly produced by cancer cells, macrophages and other phagocytic cells. Genetic polymorphisms are known in several cytokine genes, which result in altered expression. In the present association study, we investigated the association of 14 functional polymorphisms in 11 cytokines genes with BCC risk in 529 BCC cases and 532 healthy controls. We have also tested the possible interactions between the genetic variants and three known risk factors for BCC: skin complexion, sun effect and skin response to sun exposure. We did not observe any statistically significant association between SNPs and BCC risk. However, we found that, in a subgroup of subjects more prone to skin burns, carriers of at least one copy of the G allele of rs1800629 (TNF) had an increased risk of BCC [odds ratio (OR) = 2.40, 95% confidence interval (CI) 1.38-4.16, P = 0.0005]. Moreover, in subjects less prone to sunburns, we observed that carriers of the C allele of rs1143627 (IL1B) showed a decreased risk (OR = 0.53, 95% CI 0.34-0.82, P = 0.0019). In conclusion, we found that two polymorphisms in inflammatory genes interacting with environmental risk factors could modulate BCC risk.

Metastatic melanoma is a fatal disease due to the lack of successful therapies and biomarkers for early detection and its incidence has been increasing. Genetic studies have defined recurrent chromosomal aberrations, suggesting the location of either tumor suppressor genes or oncogenes. Transcription factor 21 (TCF21) belongs to the class A of the basic helix-loop-helix family with reported functions in early lung and kidney development as well as tumor suppressor function in the malignancies of the lung and head and neck. In this study, we combined quantitative DNA methylation analysis in patient biopsies and in their derived cell lines to demonstrate that TCF21 expression is downregulated in metastatic melanoma by promoter hypermethylation and TCF21 promoter DNA methylation is correlated with decreased survival in metastatic skin melanoma patients. In addition, the chromosomal location of TCF21 on 6q23-q24 coincides with the location of a postulated metastasis suppressor in melanoma. Functionally, TCF21 binds the promoter of the melanoma metastasis-suppressing gene, KiSS1, and enhances its gene expression through interaction with E12, a TCF3 isoform and with TCF12. Loss of TCF21 expression results in loss of KISS1 expression through loss of direct interaction of TCF21 at the KISS1 promoter. Finally, overexpression of TCF21 inhibits motility of C8161 melanoma cells. These data suggest that epigenetic downregulation of TCF21 is functionally involved in melanoma progression and that it may serve as a biomarker for aggressive tumor behavior.

Background: Basal cell carcinoma (BCC) of the skin is the most common neoplasm among the Caucasian population of the western world. Ultraviolet (UV) radiation-induced p53 activation promotes cutaneous pigmentation by increasing transcriptional activity of pro-opiomelanocortin (POMC) in the skin. Induction of POMC/α-melanocyte-stimulating hormone (α-MSH) activates the melanocortin 1 receptor (MC1R), resulting in skin pigmentation. The tumor suppressor p53 is a key player in stress responses that preserve genomic stability, responding to a variety of insults including DNA damage, hypoxia, metabolic stress and oncogene activation. Malfunction of the p53 pathway is an almost universal hallmark of human tumors. Polymorphisms in the gene encoding p53 (TP53) alter its transcriptional activity, which in turn may influence the UV radiation-induced tanning response., Objective: The aim of the present work is to test association between POMC and TP53 genetic variability, the possible interplay with host factors and the risk of basal cell carcinoma of skin., Methods: We covered the variability of the two genes we used 17 tagging polymorphisms in 529 BCC cases and 532 healthy controls. We have also tested the possible interactions between the genetic variants and three known risk factors for BCC: skin complexion, sun effect and skin response to sun exposure., Results: We did not observe any statistically significant association between SNPs in these two genes and BCC risk overall, nor interactions of SNPs with known BCC risk factors. However we found that, in the group of subjects with lower sun exposure, carriers of one copy of the C allele of the TP53 SNP rs12951053 had a decreased risk of BCC (OR=0.28, 95% CI 0.12-0.62, P=0.002)., Conclusions: We have observed that the interplay of an environmental risk factor and one polymorphism in TP53 gene could modulate the risk of BCC., (Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Genetic variants in DNA repair enzymes contribute to the susceptibility to cutaneous melanoma; consequently, we analyzed whether common nonsynonymous single-nucleotide polymorphisms in DNA repair enzyme genes might also influence the course of disease. To this end, we determined eight polymorphisms of seven different DNA repair enzymes in 742 patients with cutaneous melanoma, and correlated these with overall survival. Univariate Cox proportional hazards model analyses revealed that ERCC5 (XPG) 1104 His/His was significantly associated with impaired survival. Indeed, the univariate hazard ratio (HR) was 2.8 times higher for patients with ERCC5 1104 His/His (P<0.001) compared with ERCC5 1104 Asp/Asp. Accordingly, the 5-year survival rate was 55% (95% confidence interval 43-71) for patients with ERCC5 1104 His/His, whereas 82% (95% confidence interval 78-86) of patients with ERCC5 1104 Asp/Asp were still alive at this time. Importantly, adjusted Cox regression analysis not only confirmed ERCC5 1104 His/His as an independent prognostic factor (multivariate HR=4.5; P<0.001), but also revealed the significant impact of ERCC2 (XPD) 751 Gln/Gln on prognosis, with a 2.2-fold increased HR compared with ERCC2 751 Lys/Lys (P=0.009). Thus, ERCC5 codon 1104 and ERCC2 codon 751 polymorphisms are independent prognostic factors in patients with cutaneous melanoma.

The growth rate (GR) of melanomas is not uniform. A fast-growing subtype has been identified and seems to have a role in the stabilization of the mortality rates because of melanoma. To examine features associated with fast-growing melanomas (FGMs) and to determine the relationship between the GR and well-recognized prognostic factors of melanoma, a series of 386 new invasive cutaneous melanomas seen during 2004-2009 were retrieved from our database. The GR was calculated according to earlier published studies. FGMs were defined as those whose GR was greater than 0.49 mm per month. Differences in clinical, epidemiological, and pathological features were evaluated. Correlations between the GR, tumor thickness, and mitotic rate were also analyzed. FGMs were significantly more prevalent among patients aged over 65 years and with a higher rate of past personal history of nonmelanoma skin cancer. This subtype was over-represented among melanomas located on both nonexposed and usually exposed skin and was less related to earlier sunburns. Patients with FGMs presented with more aggressive pathological features and had more advanced disease with sentinel node analysis affected in up to 35% of cases. There was a strong positive correlation between the GR and tumor thickness (r=0.762), and mitotic rate (r=0.542). This study was limited by being retrospective in nature. FGMs are a highly aggressive subtype of melanomas that seem to develop after at least two routes, one related to chronic sun exposure and another unrelated to the sun. Older patients have a higher predisposition to develop this kind of tumor. This variant warrants specific strategies to improve primary and secondary prevention.

Skin pigmentation is one of the most overt human physical traits with consequences on susceptibility to skin cancer. The variations in skin pigmentation are dependent on geographic location and population ethnicity. Skin colouration is mainly due to the pigmentation substance melanin, produced in specialized organelles (melanosomes) within dendritic melanocytes, and transferred to neighbouring keratinocytes. The two types of melanin synthesized in well defined chemical reactions are the protective dark coloured eumelanin and the sulphur containing light red-yellow pheomelanin. The events leading to the synthesis of melanin are controlled by signalling cascades that involve a host of genes encoding ligands, receptors, transcription factors, channel transporters and many other crucial molecules. Several variants within the genes involved in pigmentation have been associated with high risk phenotypes like fair skin, brown-red hair and green-blue eyes. Many of those variants have also been implicated in the risk of various skin cancers. The variants within the key pigmentation gene, melanocortin-receptor 1 (MC1R), in particular have been ubiquitously linked with high risk traits and skin cancers involving both pigmentary and non-pigmentary functions and likely interaction with variants in other genes. Many of the variants in other genes, functional in pigmentation pathway, have also been associated with phenotypic variation and risk of skin cancers. Those genes include agouti signalling protein (ASIP), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), oculocutaneous albinism II (OCA2), various solute carrier genes and transporters. Most of those associations have been confirmed in genome wide association studies that at the same time have also identified new loci involved in phenotypic variation and skin cancer risk. In conclusion, the genetic variants within the genes involved in skin pigmentation besides influencing phenotypic traits are important determinants of risk of several skin cancers. However, ultimate risk of skin cancer is dependent on interplay between genetic and host factors., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Single-nucleotide polymorphisms in different DNA-repair genes are reported to modulate risk of various cancers including melanoma. We genotyped DNA from 1186 melanoma patients and 1280 healthy controls for 13 different polymorphisms in eight DNA-repair genes. Data analyses showed that none of the polymorphisms except T241M XRCC3 was associated with an increased risk for cutaneous melanoma. Carriers of the variant alleles were associated with a decreased risk (OR 0.83; 95% CI, 0.79-0.98). Three additional polymorphisms together with T241M XRCC3 that tagged the entire gene region and the neighbouring genes KLC1, ZFYVE21 and PPP1R13B were not associated with the disease risk; neither were the inferred haplotypes. Imputation showed association of comparable magnitude with 11 non-genotyped neighbouring polymorphisms. Finally, the combination of results for all polymorphisms genotyped in the present study with published data suggests that none of the investigated polymorphisms was associated with melanoma susceptibility. We conclude that 13 non-synonymous polymorphisms in eight DNA-repair genes that are frequently investigated with respect to modulation of cancer risk in populations are not associated with susceptibility to cutaneous melanoma., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We performed DNA microarray-based comparative genomic hybridization to identify somatic alterations specific to melanoma genome in 60 human cell lines from metastasized melanoma and from 44 corresponding peripheral blood mononuclear cells. Our data showed gross but nonrandom somatic changes specific to the tumor genome. Although the CDKN2A (78%) and PTEN (70%) loci were the major targets of mono-allelic and bi-allelic deletions, amplifications affected loci with BRAF (53%) and NRAS (12%) as well as EGFR (52%), MITF (40%), NOTCH2 (35%), CCND1 (18%), MDM2 (18%), CCNE1 (10%), and CDK4 (8%). The amplified loci carried additional genes, many of which could potentially play a role in melanoma. Distinct patterns of copy number changes showed that alterations in CDKN2A tended to be more clustered in cell lines with mutations in the BRAF and NRAS genes; the PTEN locus was targeted mainly in conjunction with BRAF mutations. Amplification of CCND1, CDK4, and other loci was significantly increased in cell lines without BRAF-NRAS mutations and so was the loss of chromosome arms 13q and 16q. Our data suggest involvement of distinct genetic pathways that are driven either through oncogenic BRAF and NRAS mutations complemented by aberrations in the CDKN2A and PTEN genes or involve amplification of oncogenic genomic loci and loss of 13q and 16q. It also emerges that each tumor besides being affected by major and most common somatic genetic alterations also acquires additional genetic alterations that could be crucial in determining response to small molecular inhibitors that are being currently pursued.

The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population.

Variation within the melanocortin receptor 1 (MC1R) gene, that influences phenotypic traits and susceptibility to melanoma, is abundant across the populations. We assessed and compared the risk of melanoma in 2 European populations, German and Spanish, by genotyping MC1R variants through direct DNA sequencing from 1,185 melanoma cases and 1,582 controls. The presence of any variant in both populations was associated with a significantly increased risk of melanoma (odds ratio OR = 1.67, 95% confidence interval CI 1.40-1.99). The population attributable fractions (PAF) associated with the MC1R variants in both populations was over 25%. However, the results showed a statistically significant (p < 0.0001) higher frequency of MC1R variants in the German (70%) than in the Spanish population (60%). The red-hair colour (RHC) variants, though associated with increased risk in both populations, were more common in the German than in the Spanish population (p < 0.0001). Interestingly, non-RHC variants increased the disease risk in the Spanish (OR = 1.60, 95% CI 1.20-2.14) but not in the German population (OR = 1.07, 95% CI 0.80-1.44). Although RHC variants explained a major proportion of the observed PAF in the German population, in the Spanish population the major contributor to the PAF was the non-RHC V60L variant. We also observed reduced historic linkage disequilibrium between the variants V92M and T314T in the gene in German melanoma cases. In conclusion, our data underscored the unambiguous importance of the MC1R variants towards the population burden of melanoma. However, the variants that are associated with the disease differ between the investigated populations.

In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.