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Nevus count is highly determined by inherited variants and has been associated with the origin of melanoma. De novo melanomas (DNMMs) are more prevalent in patients with a low nevus count and have distinctive dermoscopic features than nevus-associated melanomas. We evaluated the impact of nine single nucleotide polymorphisms (SNPs) of MTAP (rs10811629, rs2218220, rs7023329 and rs751173), PLA2G6 (rs132985 and rs2284063), IRF4 (rs12203592), and PAX3 (rs10180903 and rs7600206) genes associated with nevus count and melanoma susceptibility, and the MC1R variants on dermoscopic features of 371 melanomas from 310 patients. All MTAP variants associated with a low nevus count were associated with regression structures (peppering and mixed regression), blue-whitish veil, shiny white structures, and pigment network. SNPs of PLA2G6 (rs132985), PAX3 (rs7600206), and IRF4 (rs12203592) genes were also associated with either shiny white structures or mixed regression (all corrected p-values ≤ .06). Melanomas from red hair color MC1R variants carriers showed lower total dermoscopy score (p-value = .015) and less blotches than melanomas from non-carriers (p-value = .048). Our results provide evidence that germline variants protective for melanoma risk and/or associated with a low nevus count are associated with certain dermoscopic features, more characteristic of de novo and worse prognosis melanomas., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The prognostic role of PDL1 expression, CD8+ and FoxP3+ lymphocytes in vulvar melanomas has not been studied. We correlated PDL1 expression and CD8+ and FoxP3+ immune infiltrates with clinicopathologic variables and patient outcomes in a series of 75 vulvar melanomas. Tumoral PDL1 expression (>5%) was seen in 23% of cases. By Fisher exact test, PDL1 expression and peritumoral FoxP3+ lymphocytes significantly correlated with less disease-specific death. By linear regression analysis, correlations between tumoral PDL1 expression with the density of tumoral CD8+ and peritumoral CD8+ lymphocytes, tumoral FoxP3+ with tumoral CD8+ lymphocytes, and peritumoral FoxP3+ with peritumoral CD8+ lymphocytes were observed. By univariate analyses, tumor thickness >4 mm predicted poorer progression-free survival, melanoma-specific survival, and overall survival. PDL1 expression >5% and peritumoral CD8+, peritumoral FoxP3+, and tumoral FoxP3+ lymphocytes correlated with better overall survival. By multivariate analyses, high peritumoral FoxP3+ lymphocytes independently predicted better melanoma-specific survival (P = .023), and tumor thickness independently predicted poorer progression-free survival (P = .05) and overall survival (P = .039). In conclusion, our study shows that, independent from tumor thickness, an increased density of peritumoral FoxP3+ lymphocytes may positively impact survival in a subset of vulvar melanomas. Tumoral PDL1 expression correlated with tumoral as well as peritumoral CD8+ and FoxP3+ lymphocytes, supportive of an adaptive immune response. Although the frequency of PDL1 expression is low in vulvar melanoma, its expression may identify a subset of vulvar melanoma that might respond to immunotherapy., (Copyright © 2018. Published by Elsevier Inc.)

The melanocortin 1 receptor (MC1R) is a highly polymorphic gene. The loss-of-function MC1R variants ("R") have been strongly associated with red hair color phenotype and an increased melanoma risk. We sequenced the MC1R gene in 175 healthy individuals to assess the influence of MC1R on nevus phenotype. We identified that MC1R variant carriers had larger nevi both on the back [p-value = .016, adjusted for multiple parameters (adj. p-value)] and on the upper limbs (adj. p-value = .007). Specifically, we identified a positive association between the "R" MC1R variants and visible vessels in nevi [p-value = .033, corrected using the FDR method for multiple comparisons (corrected p-value)], dots and globules in nevi (corrected p-value = .033), nevi with eccentric hyperpigmentation (corrected p-value = .033), a high degree of freckling (adj. p-value = .019), and an associative trend with presence of blue nevi (corrected p-value = .120). In conclusion, the MC1R gene appears to influence the nevus phenotype., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The expansion of CAG repeats (≥36 CAG) in the HTT gene is the only known genetic cause of Huntington's disease (HD) and the main determinant of the course of the disease. The length of the expanded CAG repeats correlates inversely with the age of onset (AOO) but does not completely determine it. We investigated the role of the melanocortin 1 receptor (MC1R) gene as a modifier factor of AOO in 600 HD patients from Spain. We sequenced the entire region of the MC1R gene and analyzed all the nonsynonymous MC1R genetic variants with a minor allele frequency of at least 0.01 in HD patients. The variability in AOO attributable to the CAG repeats and MC1R polymorphisms was evaluated using a multiple linear regression model. We found that the loss-of-function p. R151C MC1R polymorphism has a significant influence on the AOO (P = 0.004; Bonferroni-corrected P = 0.032) which explains 1.42% of the variance in AOO that cannot be accounted for by the expanded CAG repeat. Our results suggest that the MC1R gene could modify the AOO in Spanish HD patients and encourage the evaluation of loss-of-function MC1R polymorphisms in other HD populations with a higher frequency of these MC1R polymorphisms.

Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15-year-old female diagnosed with AJCC stage IB non-ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAF V 600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma-predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable., (© 2017 The Authors. Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Inherited genetic factors may modulate clinical outcome in melanoma. Some low-to-medium risk genes in melanoma susceptibility play a role in melanoma outcome. Our aim was to assess the role of the functional IRF4 SNP rs12203592 in melanoma prognosis in two independent sets (Barcelona, N = 493 and Essen, N = 438). Genotype association analyses showed that the IRF4 rs12203592 T allele increased the risk of dying from melanoma in both sets (Barcelona: odds ratio [OR] = 6.53, 95% CI 1.38-30.87, Adj p = 0.032; Essen: OR = 1.68, 95% CI 1.04-2.72, Adj p = 0.035). Survival analyses only showed significance for the Barcelona set (hazard ratio = 4.58, 95% CI 1.11-18.92, Adj p = 0.036). This SNP was also associated with tumour localization, increasing the risk of developing melanoma in head or neck (OR = 1.79, 95% CI 1.07-2.98, Adj p = 0.032) and protecting from developing melanoma in the trunk (OR = 0.59, 95% CI 0.41-0.85, Adj p = 0.004). These findings suggest for the first time that IRF4 rs12203592 plays a role in the modulation of melanoma outcome and confirms its contribution to the localization of the primary tumour., (© 2017 UICC.)

The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.

Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways.

Background: BRAF and NRAS mutation detection is crucial for advanced melanoma treatment. Our aim was to evaluate how different characteristics from formalin-fixed paraffin-embedded (FFPE) samples, age of the block or DNA concentration could influence the success of BRAF and NRAS mutational screening., Methods: DNA was obtained from 144 FFPE samples (62 primary melanoma, 43 sentinel lymph nodes [SLN] and 39 metastasis). BRAF and NRAS were sequenced by Sanger sequencing., Results: Complete sequencing results were obtained from 75% (108/144) of the samples, and at least one gene was sequenced in 89% (128/144) of them. BRAF was mutated in 55% (29/53) and NRAS in 11% (5/45) of the primary melanomas sequenced. DNA concentration correlated with the tumor area used for DNA extraction (mm2) (adj p-value<0.01, r=0.73). The age of the block did not affect sequencing success. In 60% of samples kept for more than 10 years, both BRAF and NRAS were successfully sequenced., Conclusions: Preserving sufficient tumor area in FFPE blocks is important. It is necessary to keep the FFPE blocks, no matter their age, as they are necessary to decide the best treatment for the melanoma patient.

Importance: The main high-penetrance melanoma susceptibility gene is CDKN2A, encoding p16INK4A and p14ARF. The gene MITF variant p.E318K also predisposes to melanoma and renal cell carcinoma. To date, the prevalence of MITF p.E318K and its clinical and phenotypical implications has not been previously assessed in a single cohort of Spanish patients with melanoma or in p16INK4A mutation carriers., Objectives: To evaluate the prevalence of MITF p.E318K in Spanish patients with melanoma and assess the association with clinical and phenotypic features., Design, Setting, and Participants: A hospital-based, case-control study was conducted at the Melanoma Unit of Hospital Clinic of Barcelona, with MITF p.E318K genotyped in all patients using TaqMan probes. We included 531 patients: 271 patients with multiple primary melanoma (MPM) without mutations affecting p16INK4A (wild-type p16INK4A); 191 probands from melanoma-prone families with a single melanoma diagnosis and without mutations affecting p16INK4A, and 69 probands from different families carrying CDKN2A mutations affecting p16INK4A. A population-based series of 499 age- and sex-matched cancer-free individuals from the Spanish National Bank of DNA were included as controls. Patients were recruited between January 1, 1992, and June 30, 2014; data analysis was conducted from September 1 to November 30, 2014., Main Outcomes and Measures: The genetic results of the MITF p.E318K variant were correlated with clinical and phenotypic features., Results: Among the 531 patients, the prevalence of the MITF p.E318K variant was calculated among the different subsets of patients included and was 1.9% (9 of 462) in all melanoma patients with wild-type p16INK4A, 2.6% (7 of 271) in those with MPM, and 2.9% (2 of 69) in the probands of families with p16INK4A mutations. With results reported as odds ratio (95% CI), the MITF p.E318K was associated with an increased melanoma risk (3.3 [1.43-7.43]; P < .01), especially in MPM (4.5 [1.83-11.01]; P < .01) and high nevi count (>200 nevi) (8.4 [2.14-33.19]; P < .01). Two fast-growing melanomas were detected among 2 MITF p.E318K carriers during dermatologic digital follow-up., Conclusions and Relevance: In addition to melanoma risk, MITF p.E318K is associated with a high nevi count and could play a role in fast-growing melanomas. Testing for MITF p.E318K should not exclude patients with known mutations in p16INK4A. Strict dermatologic surveillance, periodic self-examination, and renal cell carcinoma surveillance should be encouraged in this context.

Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population., (© 2015 American Neurological Association.)

Importance: BRAF inhibitors have become the standard of care in metastatic BRAF-mutant melanomas. Compared with chemotherapies, BRAF inhibitors improve overall and disease-free survival and speed the recovery of symptomatic patients with metastatic disease. The most worrisome finding is the possible development of resistance to new malignant tumors., Observations: A patient in her 30s developed massive BRAFV600E melanoma metastasis during her 30th week of pregnancy. After emergency cesarean delivery, oral dabrafenib treatment was initiated, and a partial radiologic response was confirmed within 1 month. At dermatologic digital follow-up aided by confocal microscopy 8 weeks after initiation of dabrafenib treatment, 4 melanomas were detected. Unfortunately, within the next month, the melanoma rapidly progressed. The 4 new melanomas were wild-type BRAFmelanomas, whereas the new metastasis carried a different BRAF mutation (S467L)., Conclusions and Relevance: Cutaneous malignant tumors are the most frequent adverse events of BRAF inhibitors; therefore, strict dermatologic surveillance in a referral center aided by digital follow-up is mandatory, especially when multiple nevi are present and these drugs are used in an adjuvant setting. In view of our findings, the pathogenesis of the development of new melanomas seems to be different from therapy resistance. Whether paradoxical RAF activation could explain these BRAF wild-type secondary malignant tumors is still unknown.

Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson's, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.