Pigment Cell & Melanoma Research

BackgroundThere are no widely accepted pediatric guidelines on who should undergo biopsy of the nail apparatus to screen for subungual melanoma (SUM). Reported cases of pre-adolescent children diagnosed with SUM presenting as melanonychia remain controversial. Further, observed age differences in the incidence of acral lentiginous melanoma are complicated by reported ethnic differences in adult prevalence and survival rates. MethodsWe conducted a retrospective chart review of Rady Childrens Hospital San Diego, a tertiary hospital system, with over 2 million patients in its electronic health records to identify patients diagnosed with melanonychia younger than 12 years and biopsies in these children, between January 1, 2010, and July 31, 2021. ResultsThere were 623,805 patients younger than 12 years of age seen in the outpatient setting. Average age was 7.2 years for melanonychia diagnosis, and 5.1 years for those biopsied. Nail apparatus biopsies were performed in 22 different individuals and involved the hand 17/22 (77%) and the foot 5/22 (23%). The presence of Hutchinsons sign was documented in 9/22 (41%) patients. Males were diagnosed with melanonychia and underwent biopsy more often than females. Many of the biopsies were performed in Hispanic/Latino 11/22 (50%) and Asian/Pacific Islander 3/22 (14%) patients. DiscussionRegardless of reported ethnicity, biopsy of nail apparatus is highly unlikely to uncover invasive ALM in children younger than 12 years. Prospective studies are needed to understand how incidence of melanonychia, age, gender, and ethnicity/race influence parental and clinicians perceptions of melanoma risk.

BackgroundSome pulse oximeters perform worse in people with darker skin, and this may be due to inadequate diversity of skin pigment in device development study cohorts. Guidance is needed to accurately and equitably characterize skin pigment to ensure diversity in research cohorts. We tested multiple methods for characterizing skin pigment to assess comparability and impact on cohort diversity. ObjectivesO_LIAssess reliability and comparability of common skin pigment measurement methods C_LIO_LICompare findings from different anatomical sites C_LIO_LIDemonstrate that pigment cannot be assumed from US National Institutes for Health (NIH) race categories C_LI MethodsWe used three subjective methods (perceived Fitzpatrick pFP, Monk Skin Tone MST and Von Luschan VL) and two objective methods (Konica Minolta CM-700d spectrophotometer and Delfin Skin Color Catch DSCC colorimeter) for individual typology angle (ITA), across multiple measurement sites in adults. We calculated {Delta}E to estimate operator perceptibility thresholds for subjective methods and to determine reproducibility for objective methods. We used each method to categorize participants as light, medium, or dark and compared the impact of method selection on cohort diversity. ResultsWe studied 789 participants, with 33,856 assessments. The MST had the widest luminosity range, and VL had the least discernible adjacent categories. With dark defined as ITA <-30{degrees}, 14% of participants were categorized dark as compared to 26% by pFP or 16% by MST. Approximately half of the dark cohort had an ITA <-50{degrees}. With an ITA threshold <-50{degrees}, only 7% of the cohort was categorized as dark. When Black or African American self-identification was used to define dark, 23% of the cohort was categorized as such. Each self-assigned NIH race category included a wide range of ITA and subjective scale categories. Both ITA and L* from the KM-700d and DSCC demonstrated strong correlation ( > 0.7). ConclusionCommon methods for skin pigment characterization, especially the use of race or subjective scales, have significant limitations. When applied to the same cohort, different methods yield significantly different results, and some may overestimate diversity. Previously published ITA thresholds for defining dark skin are too light and lead to underrepresentation of people with darker skin.

BackgroundDistinguishing benign proliferative nodules (PNs) from melanoma arising within congenital melanocytic nevi remains a major diagnostic challenge. Copy number alteration (CNA) analysis is widely used to support classification, but current criteria were developed using array comparative genomic hybridization (aCGH). The performance of alternative platforms such as shallow whole-genome sequencing (sWGS) and methylation arrays in this setting is poorly defined. ObjectivesThe objective of this study is to compare CNA profiles obtained from aCGH, sWGS, and methylation arrays in atypical nodules arising within congenital nevi, and to correlate these molecular findings with clinical outcomes. MethodsSixteen samples from fourteen patients were retrospectively analyzed using all three platforms. CNAs were cataloged, concordance across methods was quantified using the Jaccard index, and molecular classifications were compared. Clinical follow-up was reviewed to provide clinical context. ResultsaCGH detected 39 CNAs, sWGS 60, and methylation profiling 66. Concordance was highest between sWGS and methylation (mean Jaccard 0.67), followed by aCGH versus sWGS (0.64) and aCGH versus methylation (0.49). Cases with high aneuploidy demonstrated strong cross-platform agreement, whereas low-burden lesions exhibited greater variability between methods. Divergent molecular classifications were observed in six cases. ConclusionsWhile all methods reliably detect broad chromosomal changes, sWGS and methylation arrays identify many additional focal CNAs that may not align with CGH-based diagnostic criteria. Until platform-specific thresholds are established, aCGH remains the most conservative and clinically validated approach for evaluating proliferative nodules in congenital nevi. SIGNIFICANCEAccurate molecular classification of melanocytic proliferations in congenital nevi is essential but challenging, particularly in patients with multiple proliferative nodules. This study provides the first systematic comparison of aCGH, sWGS, and methylation-based CNA profiling in this setting. We show that higher-resolution platforms detect substantially more focal aberrations, which can lead to discordant and potentially overcalled malignancy assessments when applying CGH-derived criteria. Our findings highlight the need for platform-adapted diagnostic frameworks and support continued use of CGH as the most conservative and clinically validated method for risk stratification. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=118 HEIGHT=200 SRC="FIGDIR/small/26347388v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1d7b155org.highwire.dtl.DTLVardef@1bb7081org.highwire.dtl.DTLVardef@d72e3forg.highwire.dtl.DTLVardef@11d3f0b_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundHairstyling practices are associated with the development and/or exacerbation of various forms of alopecia. Exposure to various hairstyling practices ranges but is often insufficient in current dermatologic textbooks and training curricula. We therefore conducted a survey to establish dermatologists understanding of hairstyling practices, particularly those that have been implicated in alopecia. MethodsA 34-item anonymous, electronic survey was distributed by email to 291 board-certified dermatologists and dermatology residents across the US between August 2020 and February 2021. Responses were rated on a 10-point scale to identify physician confidence in various styling practices ResultsBlack providers were more confident in both the knowledge and counseling of all hair practices (chemical straightening, heat styling, braiding, weaving, and wigs) compared to non-Black providers (p <0.001), with the exception of counseling patients on hair dyes for which no significant difference was found (p=0.337). Female providers were only more likely to indicate confidence in knowledge regarding different heat styling methods and hair dyes, and counseling of heat styling methods compared to male providers (OR 15.72, p<0.001; OR 2.47, p=0.022; OR 3.78, p=0.001 respectively) across all hair practices surveyed. Overall, 63.8% of providers reported that the majority of their knowledge on hair practices was from personal experience as opposed to formal training. LimitationsThis survey is limited by its response rate and the inability to characterize non-responders due to anonymity. ConclusionOur study highlights educational gaps in dermatologic training on hair practices, especially those more common among Black patients. Interestingly, the majority of provider knowledge came from personal experience rather than dermatologic training emphasizing the need for formalized curricula to enhance understanding among all dermatology providers.

BackgroundCutaneous melanoma incidence is rising globally, yet epidemiological data from the high ultraviolet (UV) environment in the United Arab Emirates (UAE), with its diverse expatriate population, remain scarce. This study aims to characterize the epidemiological and histopathological features of cutaneous melanoma in a large, multi-ethnic cohort in the UAE. MethodsThis cross-sectional study analyzed histopathologically confirmed cases of cutaneous melanoma diagnosed at a tertiary referral center in the UAE from January 2017 to January 2025. Patient demographics, tumor location, histologic subtype, Clark level, and Breslow thickness were extracted and analyzed. Descriptive statistics, group comparisons, and multivariable logistic regression were performed using IBM SPSS version 29.0 to identify predictors of thick melanoma (Breslow thickness >1.0 mm). ResultsA total of 597 patients met the inclusion criteria (50.8% male; mean age 47.4{+/-}12.3 years). Individuals of European ancestry constituted 73.4% of cases. Superficial spreading melanoma was the predominant subtype (58.5%), and 46.9% of tumors were thin ([&le;]1.0 mm). Males presented with significantly thicker tumors than females (Breslow thickness of 0.72{+/-}1.32 vs. 0.50{+/-}0.58 mm; p < 0.01) and exhibited distinct anatomical distributions predominant to the back and torso as compared to females with leg and foot predominance. Multivariable analysis identified nodular melanoma (OR 18.40; 95% CI [7.08, 47.86]; p < 0.001) and increasing Clark level (OR 18.50; 95% CI [8.44, 40.58]; p < 0.001) as strong independent predictors of thick melanoma. ConclusionMelanoma in the UAE disproportionately affects fair-skinned expatriates and frequently presents with sex-specific clinical patterns. These findings highlight the need for targeted public awareness initiatives to reduce melanoma morbidity and mortality in the region.

Acral melanoma (AM) is a rare subtype of melanoma associated with poor prognosis. However, inconsistent definitions--based on either anatomic location (e.g., palms, soles, subungual areas) or histopathologic subtype (e.g., acral lentiginous melanoma)--complicate prognostication, hinder treatment decision-making, and pose challenges for both clinical and translational research. This multi-institutional retrospective cohort study aimed to determine whether anatomic location or histologic subtype better predicts outcomes in AM. Distal extremity primary melanomas (n = 469) were matched 1:2 with cutaneous melanomas (CMs; n = 938). Cox proportional hazards models evaluated recurrence-free survival (RFS), melanoma-specific survival (MSS), and overall survival (OS). Of the distal tumors, 280 (59.7%) were ALMs, including 33 (11.8%) on non-subungual dorsal sites. Compared to CMs, acral surface melanomas had worse outcomes, while dorsal melanomas had similar outcomes, independent of histology. ALMs were associated with worse survival than superficial spreading melanomas (SSMs). In interaction models, ALMs on dorsal surfaces and all histologic subtypes on acral surfaces had worse MSS than non-distal SSMs. A revised definition of AM may better inform clinical management and future research.

Despite questionable accuracy, subjective methods to categorize skin color are heavily relied upon in research and medicine. Objective skin color determination is expensive requiring specialized instrumentation and interpretation. We compare three subjective approaches, i) Fitzpatrick Skin Type Scale (FST), ii) Pantone SkinTone Guide (PST) and, iii) Monk Skin Tone Scale (MST), with objectively measured skin color from a spectrophotometer in 87 volunteers to understand the limitations of each method. In agreement with others, we show that the popular FST questionnaire correlates poorly with the objective approach. However, PST color swatches provide good correlation with spectrophotometer measurements. PST consists of 110+ swatches that are inexpensive and easy to use, however, similar to other reports, the volunteers found the number of swatches overwhelming and/or excessive. We found that the recently introduced MST is not representative of reality with only 3 of the 10 color groups representing our volunteers and published populations of volunteers. In future, we propose using 9 color swatches to split the spectrum of human skin color into 10 groupings (Nottingham Skin Categories - NSC) that are representative of the global population. This new approach would be easy to implement and inexpensive in research, healthcare and cosmetics settings, and maps directly to objective, quantitative, measures taken with a spectrophotometer. For the testing and development of new optical devices, NSC would provide increased comparability between studies and ensure studies are representative of local/global populations. In the clinic NSC would be useful for dermatology, photodynamic therapy and dosage assessment for topical medicine, for example.

Skin biopsies are heavily relied upon in dermatology to diagnose cutaneous malignancies. Mastering skin biopsies and recognizing skin cancer is a core component of dermatology residency training. However, limited data exists on evaluative standards for biopsy training and residents accuracy in diagnosing skin cancer. This study aimed to analyze pre- and post-biopsy diagnostic accuracy of a second-year resident in the Harvard Combined Dermatology Residency Program from July 2021 to June 2022. This resident recorded biopsies performed in specialty dermatology clinics across three large academic centers with attending oversight and the hypothesized pre-biopsy diagnosis and the subsequent histopathologically confirmed diagnosis. Stratifying lesions into categories of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and benign and subsequently comparing the recorded pre- and post-biopsy diagnoses, it was determined that this resident correctly identified the diagnosis in 64% of the cases and correctly diagnosed all histologically confirmed skin cancers as SCC or BCC. The specificity of this resident in identifying an SCC or BCC was 56%. This study provides a preliminary foundational dataset for developing evidence-based residency training guidelines to better prepare residents for independent clinical practice. It serves as a model for providing trainees and programs with information on variations in practice patterns.

Oculocutaneous albinism (OCA) is a genetic condition associated with impaired visual acuity and increased skin cancer risk. When OCA is due to defects in melanosome ion transport, abnormally acidic conditions in the melanosome lumen inhibit tyrosinase, the critical pigment synthetic enzyme. Hence, a therapeutic approach that optimizes melanosome pH to increase pigment production presents a potential treatment for OCA and a method for decreasing skin cancer risk. Here, we report that reduction in sAC (ADCY10) activity via naturally occurring human variants in ADCY10 restores OCA pigmentation, and sAC inhibition increases melanin synthesis in both human and mouse OCA models. These findings demonstrate that targeting melanosome pH is an effective, previously untapped therapeutic strategy for OCA and elevated skin cancer risk.

Vitiligo is an acquired pigmentary disorder of the skin and mucus membranes. Previous study has demonstrated that autologous cultured epithelial grafts (ACEG) is an effective treatment for stable vitiligo. However, extraction of full-thickness skin might result in scar formation at donor site, which have hindered the wider application of this technology, especially for patients requiring large-area transplantation. Hair follicle as a source of keratinocyte and melanocyte, could be potential source of cells for preparation of autologous cultured sheet. Through culture system optimization, we have demonstrated maintenance of undifferentiated hair follicle-derived cells in feeder-independent culture system. After expansion, the hair follicle cells were directed to differentiate into a multi-layered, epidermis-like sheet. Cell identity, viability, purity, genomic stability, and antiseptic testing for hair follicle-derived epithelial sheet (HFES) were evaluated to ensure its safety. Immunofluorescence staining showed that basal keratinocytes were the main cell type of the autologous HFES. Optimization of culture conditions leads to increased melanocyte proliferation and functionality. Transcriptomic analysis confirmed upregulation of melanosome maturation genes. The proportions of cells are also similar to composition of cells under physiological conditions. Transplantation of HFES to depigmented areas in patients with stable vitiligo results in skin repigmentation. This technology provides a novel therapeutic option for vitiligo management.

Abstract: Background: More than half of metastatic melanomas arise from patients initially diagnosed with early-stage melanoma. Objective biomarkers are needed to better identify high-risk patients. Objective: To evaluate the prognostic value of multiple histopathological characteristics in predicting distant metastasis risk, in early-stage melanoma. Methods: Using data from discovery set (n=442) and a population-based validation cohort (n=306, sampled from 5,815 patients) of the Dutch Early-Stage Melanoma (D-ESMEL) study, we investigated 14 histopathological characteristics of melanoma and their tumor micro-environment (TME) in an unprecedented integration, by expert pathologist scoring and automated quantitative measurements derived from a validated automated segmentation. Results: Increased immune infiltrates (40% in cases vs. 50% in controls) were associated with lower risk of metastasis. Automated immune cell density was predictive in both the discovery set and the validation cohort, outperforming the manual pathological tumor infiltrating lymphocytes. The remaining histopathological features, including mitotic activity, did not retain independent value after controlling for current staging variables. Limitations: TME evaluation in standard Hematoxylin-Eosin slides. Conclusion: TME reaction is an important determinant of melanoma progression. The automated quantification of immune cell density appears to be a biomarker for distant metastasis risk. Further investigation into specific immune cell subtypes is required to facilitate clinical integration.

I.Cutaneous skin melanomas with wild-type BRAF alleles ("BRAF-WT melanomas") remain relatively difficult to treat, even though they typically possess driver mutations in a RAS gene or NF1. For example, these tumors respond relatively poorly to combinations of MEK and BRAF inhibitors, and their response to ICIs is muted compared to the response of BRAF-mutant melanomas. ERBB2 and ERBB4, which encode receptor tyrosine kinase genes, are necessary and sufficient for the proliferation of multiple BRAF-WT melanoma cell lines. Consequently, we have postulated that ERBB4-ERBB2 heterodimerization drives BRAF-WT melanomas. This mechanism is consistent with the observation that elevated ERBB4 transcription or ERBB4 mutations are found in a significant fraction of BRAF-WT melanoma tumor samples. Moreover, a subset of ERBB4 mutations found in BRAF-WT melanoma samples increases proliferation in a BRAF-WT melanoma cell line. Because the elevated ERBB4 transcription observed in BRAF- WT melanomas is typically insufficient to cause ligand-independent ERBB4 signaling, we have postulated that ligands for ERBB family receptors drive the elevated ERBB4-ERBB2 heterodimerization responsible for the proliferation of BRAF-WT melanoma cell lines. We have explored this hypothesis by analyzing data found in the Broad Institutes Cancer Cell Line Encyclopedia. These data suggest that some EGF family hormones are required for the proliferation of BRAF-WT melanoma cell lines. Likewise, the G11/Gq pathway, which can stimulate cleavage and maturation of EGF family hormones, is also required for the proliferation of BRAF-WT melanoma cell lines. Thus, these data suggest additional therapeutic targets in BRAF-WT melanomas. Moreover, because many uveal (ocular) melanomas possess elevated G11/Gq signaling, these data suggest that ligand stimulation of ERBB receptor signaling may contribute to uveal melanomagenesis or progression.

The genetic bases of mosaic pigmentation disorders have increasingly been identified, but these conditions remain poorly characterised, and their pathophysiology is unclear. Here, we report in four unrelated patients that a recurrent postzygotic mutation in GNA13 is responsible for a recognizable syndrome with hypomelanosis of Ito associated with developmental anomalies. GNA13 encodes G13, a subunit of {beta}{gamma} heterotrimeric G proteins coupled to specific transmembrane receptors known as G-protein coupled receptors. In-depth functional investigations revealed that this R200K mutation provides a gain of function to G13. Mechanistically, we show that this variant hyperactivates the RHOA/ROCK signalling pathway that consequently increases actin polymerisation and myosin light chains phosphorylation, and promotes melanocytes rounding. Our results also indicate that R200K G13 hyperactivates the YAP signalling pathway. All these changes appear to affect cell migration and adhesion but not the proliferation. Our results suggest that hypopigmentation can result from a defect in melanosome transfer to keratinocytes due to cell shape alterations. These findings highlight the interaction between heterotrimeric G proteins and the RHOA pathway, and their role in melanocyte function.

The molecular diagnosis of albinism is hampered by a significant number of genetic variants of unknown significance (VUS) including a majority of missense and in-frame insertion deletion variants. This contributes to the high rate of unresolved genetic diagnosis for this disease. We designed a straightforward test of missense VUS in albinism genes based on functional rescue. As a proof of concept, the assay was set up for testing variants in the TYR gene associated with oculocutaneous albinism type 1. The TYR gene was knocked-out in the human melanogenic MNT1 cell line and the resulting unpigmented clones used as host cells for rescue experiments. Selected VUS and control sequences were run through the assay. Expression of tyrosinase was quantified by Western-blot, melanin synthesis was evaluated by direct observation as well as absorbance monitoring. One VUS, p.Ser270Phe (S270F) can be classified as pathogenic as it fails to restore pigmentation, whereas rescue was achieved with D305E and A391T. The two most frequent missense VUS of TYR, S192Y and R402Q, were also tested independently or in combination confirming the pathogenic effect of their association in cis. All in all, this new assay is straightforward enough to be transposed in diagnosis laboratories and can be considered for testing variants in other albinism genes such as TYRP1 and SLC45A2.

BackgroundNon-segmental vitiligo(NSV) shows marked heterogeneity in activity, progression, and treatment response. Reliable clinical markers that predict prognosis and patient-reported outcomes are lacking. ObjectivesTo identify clinicodemographic and clinical predictors of disease extent, progression, repigmentation, treatment dependency, noticeability, and psychosocial impact in NSV. MethodsIn this prospective cohort study, 275 patients with NSV were followed for 12 months. Sixteen baseline variables, including demographic features, autoimmune history, and clinical markers (koebnerization, confetti and trichrome patterns, leukotrichia, mucosal, acral, and periorificial involvement), were recorded. Outcomes included body surface area(BSA), progression, repigmentation, treatment dependency, Vitiligo Noticeability Scale(VNS), and quality-of-life indices(VIS-22, DLQI, C-DLQI, F-VIS). Multivariable analyses and cluster analysis were performed at 6 and 12 months. ResultsMarkers of disease activity leukotrichia, trichrome and confetti lesions, koebnerization, and mucosal, acral, and periorificial involvement were strongly associated with greater BSA, poor repigmentation, higher noticeability, and treatment dependency. Leukotrichia was consistent predictor of poor repigmentation and high VNS. Family history of autoimmunity predicted progression and treatment dependency. Early-onset vitiligo showed lower disease extent but greater family-related psychosocial burden. Cluster analysis identified severe, intermediate, and mild phenotypes with distinct therapeutic responses. ConclusionsSimple clinical markers can stratify NSV patients into prognostic subgroups, enabling individualized treatment and counseling. Plain Language SummaryVitiligo behave variably in different people, some people may have slow-spreading course, while others develop widespread or persistent patches. In this study, we followed 275 people with non-segmental vitiligo for one year to find signs on the skin that could predict how the disease would behave and how it would affect daily life. We found that features such as white hair within patches (leukotrichia), speckled (confetti) or three-colored lesions (trichrome), new patches appearing after injury (koebnerization), and involvement of the lips, mouth, hands, feet were linked to more severe disease, poorer response to treatment, and greater cosmetic concern. A family history of autoimmune disease increased the risk of worsening vitiligo. Patients who developed vitiligo early in life had less skin involvement but greater emotional and family-related impact. These easily recognized signs can help doctors and patients plan treatment and set realistic expectations. Significance of the studyNon-segmental vitiligo (NSV) has a heterogeneous and unpredictable clinical course with variable progression and response to therapy. However, robust prospective data linking these markers with long-term outcomes and patient-reported measures remain limited. In our prospective cohort of 275 patients, clinical markers such as leukotrichia, trichrome and confetti lesions, koebnerization, and acral/mucosal/periorificial involvement, were strongly associated with greater disease extent, poorer repigmentation, higher treatment dependency, and increased noticeability. Leukotrichia consistently predicted poor repigmentation. Thereby, prognostic stratification can also improve patient counselling regarding expected repigmentation, treatment duration, and psychosocial burden.

The pigment melanin protects skin cells from ultraviolet (UV) radiation induced DNA damage. However, intermediates of eumelanin are highly reactive quinones that are potentially genotoxic. In this study, we systematically investigate the effect of sustained elevation of melanogenesis and map the consequent cellular repair response of melanocytes. Pigmentation increases DNA damage, causes cell cycle arrest, and invokes translesion polymerase Pol {kappa} for DNA repair in primary human melanocytes, as well as mouse melanoma cells. Confirming the causal link, CRISPR-based genetic ablation of tyrosinase, the key melanin synthesizing enzyme results in depigmented cells with low Pol {kappa} levels. However, silencing of Pol {kappa} in pigmenting cells results in unchecked proliferation despite the presence of damaged DNA, that could potentially lead to genome instability. Thereby, our results indicate Pol {kappa} to be a necessary evil to resolve melanin induced damage. Error-prone repair by Pol {kappa} in part explains the mutational landscape observed in human melanoma. Thus, our study illuminates a hitherto unknown dark side of melanin and identifies (eu)melanogenesis as a key missing link between tanning response and mutagenesis mediated via the Pol {kappa}-based low fidelity DNA repair response of melanocytes. Key HighlightsO_LISustained melanogenesis causes DNA damage in melanocytes C_LIO_LIMelanogenesis elicits replication stress and translesion repair by Pol {kappa} C_LIO_LIPol {kappa} resolves melanin-induced DNA damage and suppresses genome instability C_LIO_LIExpression of Pol {kappa} correlates with mutational load in human melanoma C_LI

Structured AbstractO_ST_ABSImportanceC_ST_ABSThe genetic architecture of disease risk may not be independent of social determinants. This can be leveraged to investigate for causality. ObjectiveTo investigate for a possible causal relationship between socioeconomic status (SES) and melanoma in situ (MIS) based on their genetic architectures. DesignGenetic correlation study SettingMulticenter and population-based data sources. ParticipantsThe Ingold et al., 2024 GWAS summary statistic dataset is derived from 3,564 MIS cases, 10,552 invasive melanoma (MM) cases, and 1,022,070 melanoma-free controls. Individuals with both MIS and MM were only included as MM cases. The Kweon et al., GWAS summary statistic dataset on income, a proxy for SES, is derived from an effective sample size of 668,288 individuals. Main Outcome(s) and Measure(s)Genetic correlation between MIS, MM, and SES. ResultsWe obtained European genomic ancestries-based GWAS summary statistics for MIS (3,564 cases and 1,022,070 melanoma-free controls), MM (10,552 cases and 1,022,070 melanoma-free controls), and SES (668,288 individuals). We identify a positive and significant genetic correlation between MIS and SES (0.14, 95% CI 0.06 to 0.21; p = 5.55 x 10-04) but not MM and SES (0.05, 95% CI -0.01 to 0.11; p = 0.11). The genetic architecture of MIS subtracting that of MM (MIS-MM) remained positively and significantly correlated with the genetic architecture of SES (0.23, 95% CI 0.07 to 0.39; p = 4.18 x 10-03). In contrast, the genetic architecture of MM subtracting that of MIS (MM-MIS) is negatively correlated with the genetic architecture of SES (-0.24, 95% CI -0.42 to -0.06; p = 8.01 x 10-03). Finally, taking a Mendelian Randomization approach, we identify consistent evidence for a causal pathway between MIS and SES but not MM and SES. Conclusions and RelevanceThe genetic architecture of SES correlates with that of MIS but not MM. There is also evidence for a causal link between SES and MIS. Both these findings support an overdiagnosis of MIS. Importantly, our results demonstrate genetic risk scores for disease are not inherently independent of social determinants of diagnosis. Clinical application of genetics-based risk stratification without consideration of social determinants may have limited utility. Key PointsO_ST_ABSQuestionC_ST_ABSIs socioeconomic status genetically correlated with melanoma in situ and is there any evidence for a causal relationship? FindingsIn this genetic correlation study based on data from 3,564 melanoma in situ cases, 10,552 invasive melanoma cases, 1,022,070 melanoma-free controls, and 668,288 individuals with income data; we identify a positive and significant genetic correlation between socioeconomic status and melanoma in situ but not invasive melanoma. We also identify Mendelian Randomization-based evidence for a causal relationship between socioeconomic status and melanoma in situ but not invasive melanoma MeaningThe genetic architecture of disease risk is not independent of social determinants of diagnosis. Clinical application of genetics-based risk stratification without consideration of social determinants may have limited utility.

Cutaneous squamous cell carcinoma (SCC) can be time-consuming to treat with Mohs micrographic surgery (MMS) due to the need for intraoperative frozen section (FS) preparation. Two-photon fluorescence microscopy (TPFM) can generate H&E-equivalent images from fresh tissue specimens in a fraction of this time. To determine the accuracy of TPFM for the evaluation of squamous cell carcinoma in MMS margins compared to conventional FS Mohs slide preparation. TPFM was used to image 144 first stage MMS margins from patients being treated for SCC. A Mohs surgeon reviewed 44 training images and then evaluated 100 margins. After a delay, the same surgeon evaluated the corresponding FS slides. Pairs of TPFM and FS slides were reviewed by an expert dermatopathologist to form a consensus diagnosis. Agreement with consensus diagnosis as assessed by an independent dermatopathologist. 3 margins (3%) unequivocally disagreed with the consensus on TPFM and 2 margins (2%) disagreed on FS. The sensitivity and specificity of TPFM were 95.1% and 98.2%, respectively. This study demonstrates that slide-free histology can be interpreted equivalently to conventional Mohs slide processing by both MMS surgeons and dermatopathologists with minimal training.

Melanoma is an aggressive cancer typically arising from transformation of melanocytes residing in the basal layer of the epidermis, where they are in direct contact with surrounding keratinocytes. The role of keratinocytes in shaping the melanoma tumor microenvironment remains understudied. We previously showed that temporary loss of the keratinocyte-specific cadherin, Desmoglein 1 (Dsg1) controls paracrine signaling between normal melanocytes and keratinocytes to stimulate the protective tanning response. Here, we provide evidence that melanoma cells hijack this intercellular communication by secreting factors that keep Dsg1 expression low in surrounding keratinocytes, which in turn generate their own paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signaling. Evidence suggests a model whereby paracrine signaling from melanoma cells increases levels of the transcriptional repressor Snai2 (Slug), and consequently decreases the Dsg1 transcriptional activator Grhl1 (Grainyhead like 1), a known promoter of epidermal differentiation and barrier function. Together, these data support the idea that paracrine crosstalk between melanoma cells and keratinocytes resulting in chronic keratinocyte Dsg1 reduction contributes to melanoma cell movement associated with tumor progression.

BackgroundCorticotropin-releasing hormone (CRH) is involved in the regulation of immunological and cellular processes. Recently, CRH has been found to be expressed in skin cancers, where its expression appears to correlate with the degree of malignancy. ObjectiveThis study correlates CRH expression in melanoma metastases with patient survival and compares the intensity of CRH expression in melanoma to that in less aggressive skin cancer entities. MethodsTissue microarrays with cores from 94 melanomas and 40 melanocytic nevi and 51 slides from 41 basal cell carcinomas (BCC) and 10 squamous cell carcinomas (SCC) were immunohistochemically stained for CRH. The intensity of CRH expression in melanoma metastases was stratified by sex and correlated with patient survival. Furthermore, proliferation and apoptosis were assessed in CRH-stimulated A431 cells using enzyme-linked immunosorbent assays and an apoptosis detection kit. ResultsThe intensity of CRH expression was higher in primary melanomas than in melanocytic nevi. Higher CRH expression was also found in melanoma metastases from women compared to men. However, higher CRH expression was correlated with reduced overall survival only in men. Compared to melanoma, BCCs and SCCs showed weaker CRH expression, which was in line with the finding that in vitro, CRH stimulation of the A431 cells reduced their proliferative activity. ConclusionCRH does not necessarily correlate with the degree of malignancy, as semi-malignant cancers such as BCC show higher levels of CRH expression than SCCs. In melanoma, CRH expression in metastases may be an important prognostic factor for overall survival in men, which needs further evaluation. Statement of contributionMarcel Mueller and Susanne Melchers performed all experiments and wrote the first draft of the manuscript. Iris Mueller helped with the experiments and reviewed the manuscript, Jochen Utikal assembled the tissue microarrays and reviewed the manuscript, Julia Krug helped with the figures and reviewed the manuscript, and Astrid Schmieder designed and supervised the project and corrected the manuscript.