BACKGROUND: Multiple primary melanoma (MPM) is a diagnostic challenge even with ancillary imaging technologies available to dermatologists. In selected patients\' phenotypes, the use of imaging approaches can help better understand lesion characteristics, and aid in early diagnosis and management.
METHODS: Under a 5-year prospective single-center follow-up, 58 s primary melanomas (SPMs) were diagnosed in two first-degree relatives, with fair skin color, red hair, green eyes, and personal history of one previous melanoma each. Patients\' behavior and descriptive demographic data were collected from medical records. The information on the first two primary melanomas (PMs) were retrieved from pathology reports. The characteristics of 60 melanomas were collected from medical records, video dermoscopy software, and pathology reports. Reflectance confocal microscopy (RCM) was performed prior to excision of 22 randomly selected melanomas.
RESULTS: From February 2018 to May 2023, two patients underwent a pooled total of 214 excisional biopsies of suspect lesions, resulting in a combined benign versus malignant treatment ratio (NNT) of 2.0:1.0. The number of moles excised for each melanoma diagnosed (NNE) was 1.7:1.0 and 6.9:1.0 for the female and male patient respectively. The in-situ melanoma/invasive melanoma ratio (IIR) demonstrated a higher proportion of in-situ melanomas for both patients. From June 2018 to May 2023, a total of 58 SPMs were detected by the combination of total body skin exam (TBSE), total body skin photography (TBSP), digital dermoscopy (DD), and sequential digital dermoscopy imaging (SDDI) via comparative approach. The younger patient had her PM one month prior to the second and third cutaneous melanomas (CMs), characterizing a case of synchronous primary CM. The male older relative had a total of 7 nonsynchronous melanomas.
CONCLUSIONS: This CM cohort is composed of 83.3% in-situ melanoma and 16.7% invasive melanoma. Both patients had a higher percentage of SPM with clinical nevus-like morphology (84.5%), global dermoscopic pattern of asymmetric multiple component (60.3%) and located on the lower limbs (46.6%). When RCM was performed prior to excision, 81% of SPM had features suggestive of malignancy. As well, invasive melanomas were more frequent in the lower limbs (40%). In the multivariate model, for the two high-risk patients studied, the chance of a not associated with nevus (\"de novo\") invasive SPM diagnosis is 25 times greater than the chance of a diagnosis of a nevus-associated invasive SPM.

The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden.

Inherited variation in MC1R imparts low to moderate risk of melanoma. Research on genetic risk recall, factors predicting recall, and whether recall influences adoption of preventive behaviors is limited.
Participants (n = 447) enrolled in a melanoma precision prevention trial were provided with MC1R risk information (average or higher) and after 6 and 12 months, were asked to recall their genetic risk. Predictors of recall were identified using backward stepwise selection. Intervention effects were reassessed after stratifying by recall.
Participants at higher risk were 2 to 3 times more likely to misremember or not recall than participants with average risk. Misremembering was almost exclusively observed among participants at higher risk. Among the participants with average risk, lower health numeracy and not completing the telephone follow-up were associated with not recalling or misremembering. Among the participants at higher risk, lower education was associated with not recalling and lower perceived comparative chance of developing melanoma was associated with misremembering. In general, participants at higher risk who correctly recalled had modestly stronger intervention effects on sun protection behaviors than those who misremembered or did not recall.
Future studies should examine different strategies to increase genetic risk recall, which may result in improved behavioral outcomes, especially among participants with lower education and health numeracy.

Skin cancer incidence is increasing among Hispanics, who experience worse outcomes than non-Hispanic Whites. Precision prevention incorporating genetic testing for MC1R, a skin cancer susceptibility marker, may improve prevention behavior.
Hispanic participants (n=920) from Tampa, FL and Ponce, PR, were block-randomized within MC1R higher- and average-risk groups to precision prevention or generic prevention arms. We collected baseline information on demographics, family history of cancer, phenotypic characteristics, health literacy, health numeracy, and psychosocial measures. Participants reported weekday and weekend sun exposure (in hours), number of sunburns, frequency of five sun protection behaviors, intentional outdoor and indoor tanning, and skin examinations at baseline, three months, and nine months. Participants also reported these outcomes for their eldest child ≤10 years old.
Among MC1R higher-risk participants, precision prevention increased sunscreen use (OR=1.74, p=0.03) and receipt of a clinical skin exam (OR=6.51, p=0.0006); and it decreased weekday sun exposure hours (β=-0.94, p=0.005) and improved sun protection behaviors (β=0.93, p=0.02) in their children. There were no significant intervention effects among MC1R average risk participants. The intervention did not elevate participant cancer worry. We also identified moderators of the intervention effect among both average- and higher-risk participants.
Receipt of MC1R precision prevention materials improved some skin cancer prevention behaviors among higher-risk participants and their children and did not result in reduced prevention activities among average-risk participants. Despite these encouraging findings, levels of sun protection behaviors remained suboptimal among participants, warranting more awareness and prevention campaigns targeted to Hispanics.

Inherited variation at MC1R is associated with elevated melanoma risk among non-Hispanic whites (NHWs). MC1R genetic testing may unmask previously unrecognized disease risk, especially among individuals with few melanoma phenotypic risk factors. We recruited NHW individuals with limited phenotypic risk factors from two primary care clinics in west-central Florida. Participants (n = 1134) were randomized within MC1R genotype risk group (average/higher) to receive mailed precision prevention (i.e., intervention) or generic prevention materials. Participants reported hours of weekday and weekend sun exposure, frequency of intentional outdoor tanning and sun protection behaviors, number of sunburns, indoor tanning episodes, and skin examinations at baseline, and after 6 and 12 months. Among MC1R higher-risk participants, the intervention increased the likelihood of often or always wearing a shirt with sleeves (OR = 1.49, p = 0.03) and seeking shade or using an umbrella (OR = 1.42, p = 0.046), and it decreased the number of sunburns among their young children (β = -0.13, p = 0.03). Intervention effects were not noted among MC1R average-risk participants. Moderation analyses identified intervention effects within subgroups in average-risk and higher-risk participants. Precision prevention information conveying MC1R testing results can increase the practice of some sun protection behaviors among at-risk individuals with limited melanoma risk phenotypes and may provide a cross-generational tool to counteract increasing incidence of melanoma.

The coat colour of fallow deer is highly variable and even white animals can regularly be observed in game farming and in the wild. Affected animals do not show complete albinism but rather some residual pigmentation resembling a very pale beige dilution of coat colour. The eyes and claws of the animals are pigmented. To facilitate the conservation and management of such animals, it would be helpful to know the responsible gene and causative variant. We collected 102 samples from 22 white animals and from 80 animals with wildtype coat colour. The samples came from 12 different wild flocks or game conservations located in different regions of Germany, at the border to Luxembourg and in Poland. The genomes of one white hind and her brown calf were sequenced.
Based on a list of colour genes of the International Federation of Pigment Cell Societies ( http://www.ifpcs.org/albinism/ ), a variant in the MC1R gene (NM_174108.2:c.143 T > C) resulting in an amino acid exchange from leucine to proline at position 48 of the MC1R receptor protein (NP_776533.1:p.L48P) was identified as a likely cause of coat colour dilution. A gene test revealed that all animals of the white phenotype were of genotype CC whereas all pigmented animals were of genotype TT or TC. The study showed that 14% of the pigmented (brown or dark pigmented) animals carried the white allele.
A genome-wide scan study led to a molecular test to determine the coat colour of fallow deer. Identification of the MC1R gene provides a deeper insight into the mechanism of dilution. The gene marker is now available for the conservation of white fallow deer in wild and farmed animals.

Introduction: Melasma is an acquired hypermelanosis of the face. The pathogenesis of melasma is multifactorial and may be caused by interactions between genetics and the environment. Research has shown that skin pigmentation is regulated by the Melanocortin-1 Receptor gene (MC1R). In Japanese populations, Val92Met and Arg163Gln genotypes of MC1R gene polymorphisms are associated with freckles and lentigo solaris, because they have skin types II-III, but for Indonesians who are skin type IV, hyperpigmentation disorders are often melasma. Purpose: This study aimed to identify the association between Val92Met and Arg163Gln genotypes of MC1R gene polymorphisms with the incidence of melasma in a Javanese women population. Patients and methods: This study used unmatched case-control design, conducted by clinical examination and questionnaire. Data were analyzed with Chi-squared test and Odds Ratio (OR). Results: This study evaluated 158 Javanese women from 18-60 years old with 79 case and 79 control subjects. The genotype of Val92Met was found more common in melasma subjects than in non-melasma (p=0.005) with (OR2.53; 95% CI:1.21-5.29). By using a bivariate test we showed sun exposure and family history of melasma were risk factors for melasma (OR:1.99; 95% CI:1.04-3.78) and (OR:35.32; 95% CI:10.25-121.70). However, genotype of Arg163Gln was not a risk factor for the incidence of melasma (OR: 0.86; 95% CI:0.39-1.89). Conclusion: The findings showed Val92Met genotypes, sun exposure and family history were risk factors for melasma incidence. This is the first study on incidence of melasma in an Indonesian population and contributes to ongoing efforts to understand the mechanisms of melasma.

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.
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.

BACKGROUND: The extended disability severity scale (EDSS) is clinically useful in assessing disability in multiple sclerosis (MS) patients. It is also being used in studies to determine how genes and environment influence disability. However, since it has a complex relationship with functional scores and mobility and is strongly determined by disease duration its use can be limiting.
OBJECTIVE: Study associations of variables with progression described by time from disease onset until EDSS.
METHODS: We used a variable based on below/above median time from MS onset to reach a single EDSS value to define slow or fast progression. We compared patient categorization using this variable and MSSS, and in 533 patients (EDSS 1-8) and 242 of these patients with EDSS1-4, studied associations with skin type, gender, ultraviolet radiation and MC1R Asp294His.
RESULTS: Classifying patients into quartiles of slow/fast progression showed mean MSSS increased with faster progression (p<0.001). For EDSS 1-8: MSSS, late onset age and childhood sunburning were associated with fast and MC1R CG/GG(294) with slow progression. Combinations of skin type (1/2 or 3/4) with childhood weekend exposure (< or ≥median) or sunburning (yes/no) were not associated with progression. However, in patients with EDSS1-4, relative to other combinations, those with no sunburning history and types 1/2 demonstrated slow progression (odds ratio=0.15, 95% CI=0.04, 0.57).
CONCLUSIONS: This method, though a pilot, allows study of associations of variables with EDSS. It is based on local patients and could substitute for MSSS. In patients with EDSS1-4 but not 1-8, skin type 1/2 with no history of childhood sunburning was associated with slow progression. This is compatible with the view that disability develops through a first stage dependent on inflammation.

Melanocortin 1 receptor (MC1R) gene variants are a major contributor to pigmentation characteristics and the modulation of sporadic basal cell carcinoma (BCC) risk. This is a hospital-based, case-control study to investigate the association of MC1R variants and pigmentary characteristics with the risk of BCC development in a Southern European population in Greece. In total, 141 patients with BCC and 166 controls were studied. Increased BCC risk was found for the presence of 2 or more MC1R variants (OR:3.07, 95% CI:1.13-8.34), or 2 or more variants of which at least 1 was major function (OR:7.15, 95% CI:1.37-5.52), after adjustment for the \'red hair colour\' (RHC) phenotype. Increased BCC risk persisted in the presence of 2 or more MC1R variants (OR:4.15, 95% CI:1.35-12.72), after adjustment for potential confounding factors including skin color (P:0.237) and atypical nevi (OR:9.57, 95% CI:2.19-41.81, P:0.003). MC1R genotype is a risk factor for the development of BCC in Greek patients independently of pigmentary characteristics, and the combination of MC1R variants may modulate this risk.