Pigment Cell & Melanoma Research最新文献

Low density lipoprotein receptor-related protein 2 (LRP2) is a 600 kilodalton multi-ligand endocytic membrane receptor expressed in several cell types during fetal development, including neuroepithelial cells, and in select absorptive epithelial cells in the adult. In epithelial cancers, LRP2 expression is associated with a differentiated tumor cell state and better prognosis. In previous work, we found that while LRP2 is not expressed in benign naevi, it is frequently acquired in melanoma. However, the molecular drivers of LRP2 expression in melanoma and characteristics of LRP2-expressing melanoma have yet to be described. Here, we show that LRP2 expression is related to a transitory melanoma cell state defined by co-expression of melanocyte lineage and neural crest transcriptional programs. Further, we reveal that melanoma LRP2 expression is increased in T cell-inflamed tumors and is directly upregulated through interferon-gamma signaling. Correlation of melanoma LRP2 expression with clinicopathological variables demonstrates that LRP2 expression is associated with low Breslow thickness and low clinical stage in primary melanomas. Taken together, the present study describes the characteristics of LRP2-expressing melanoma and reveals interferon-gamma signaling as a novel strong positive regulator of LRP2 expression in melanoma.

Some patients with uveal melanoma (UM) show genetic cancer predisposition: ~2% harbor a pathogenic or likely pathogenic (P/LP) germline variant in BAP1 or, rarely, in 20 other cancer-associated genes. Up to 75% of patients with familial UM (FUM) lack genetic diagnosis, prompting a search beyond BAP1. We studied with exome sequencing blood samples from 106 patients with UM and higher-than-average risk of cancer (UM ≤ 45 years of age, bilateral or familial UM, or personal history of non-ocular cancer) and no P/LP variants in BAP1. Sixteen (15%; 95% confidence interval [CI] 9-23) patients carried at least one P/LP variant in dominant cancer genes (CHEK2, DDX41, FANCM, HOXB13, RAD50, SDHA, SDHB) and fifteen in recessive ones. Only CHEK2 and FANCM have previously been reported in patients with UM. Six patients (6%; 95% CI 2-12) carried multilocus P/LP variants. Their median age at diagnosis of UM was 51 (range, 22-69) years, 9 years less than the cohort median of 60 (range, 13-89). This suggests a role for co-occurring pathogenic variants and potentially multilocus inherited neoplasia allele syndrome (MINAS) in UM predisposition. None with FUM carried P/LP variants, warranting investigation of further genes, lower penetrance variants, and multi-gene heterozygosity in UM predisposition.

The progression of non-segmental vitiligo is highly unpredictable, exhibiting various phenotypes that can range from rapid progression to stability. Due to limited literature, we conducted a scoping review to identify factors influencing the outcomes of non-segmental vitiligo, focusing on disease progression, extent, and response to therapy. This review adhered to PRISMA-ScR guidelines and involved searching the PubMed and Google Scholar databases for studies published in English from January 1995 to December 2023. We included observational, retrospective, case-control, and cohort studies while excluding case reports, systematic reviews, meta-analyses, and studies on segmental vitiligo. Out of 922 records identified, 819 were screened, resulting in 792 exclusions based on titles or abstracts. Ultimately, 22 articles were selected for review after evaluating the full texts of 27 articles. Several factors were consistently linked to poorer prognoses in multiple studies: family history of vitiligo, mucosal involvement, Koebnerization, and the presence of adverse clinical markers. Age of onset yielded conflicting results regarding disease progression but showed general agreement concerning the extent of involvement. Specific lesions such as confetti-like lesions were also associated with progression in limited studies. Additionally, longer disease duration, leukotrichia, and mucosal involvement correlated with a greater body surface area affected by vitiligo, often resulting in poor repigmentation responses to medical treatments. Patients exhibiting poor prognostic markers-such as family history, mucosal lesions, or Koebnerization-should be advised to monitor for new lesions closely and consider early treatment initiation. Understanding the factors influencing the course of non-segmental vitiligo's course can guide clinicians in tailoring management strategies that reflect individual patient needs while considering the complexities associated with this condition. A prospective study with at least 1 year of follow-up is needed to comprehensively describe observed progression, along with well-defined predictors and outcome measures including temporal course patterns. Prospero Registration: CRD42023446544.

A melanoma is a malignant neoplasm that originates from melanocytes. Melanocytes are found in various body sites—they are most commonly found in the skin (including acral sites and nail units), ocular structures, and mucosal membranes. This narrative review aims to comprehensively summarize the current information available regarding several types of melanomas and to analyze the existing evidence. Despite the same origin—melanocytes—melanomas appear to be a heterogeneous neoplasm. A thorough analysis of several types of melanomas reveals differing genetics, risk factors, epidemiology, and prognosis. The most common locations for melanomas are primarily the skin, followed by ocular structures and acral sites. Mucosal melanomas occur more frequently in older individuals than cutaneous melanomas; cutaneous melanomas occur more frequently in males. Mucosal and nail unit melanomas predominantly affect females, whereas ocular melanomas occur with similar frequencies in both sexes or are slightly more common in males. The highest incidence of amelanotic cases is observed in patients with mucosal, uveal, and conjunctival melanomas. Mucosal melanomas, including conjunctival, present as multifocal lesions more often than in other affected body areas. Additionally, the poorest survival rate is observed for mucosal melanomas.

Metastatic uveal melanoma (mUM) is a rare disease associated with poor prognosis and limited therapeutic options. Recent studies showed that detecting ctDNA is feasible and can aid treatment decisions for patients with mUM. We systematically searched PubMed, EMBASE, and Cochrane databases for eligible studies published up to May 2025 that included patients with mUM and reported data on the association between ctDNA and survival outcomes (OS and PFS). Statistical analyses were performed using Review Manager 5.4 software. Of the initial 450 records, seven studies met eligibility, including 518 patients with mUM. At baseline, ctDNA positivity was associated with significantly worse PFS (HR 2.34; 95% CI 1.56–3.51; p < 0.01; I² = 0%) and OS (HR 3.32; 95% CI 2.09–5.29; p < 0.01; I² = 48%). In patients treated with tebentafusp, ctDNA clearance was associated with superior OS (HR 0.19; 95% CI 0.07–0.49; p < 0.01; I² = 46%) and any decrease in ctDNA was associated with better OS (HR 0.42; 95% CI 0.22–0.80; p < 0.01; I² = 0%). This meta-analysis underscores ctDNA as a potential predictor of worse survival in patients with mUM, highlighting its potential to refine risk stratification and guide treatment strategies.

Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO): CRD42025638076

As effective melanoma treatments have become available, utilizing isolated limb perfusion (ILP) to treat unresectable melanoma limited to the limb has decreased. However, some patients still receive long-term benefits from ILP. We aimed to identify features of the pretreatment tumor microenvironment (TME) to identify patients who may benefit from ILP. Pretreatment metastatic melanoma samples from 22 patients treated at Helsinki University Hospital with ILP from 2008 to 2018 were analyzed with multiplex immunohistochemistry (mIHC) and digital image analysis. Antibody panels evaluated the proportions of immune cells in the intratumoral and extratumoral compartments. We examined whether treatment response and median progression-free survival (PFS) after ILP correlated to findings in the TME. A statistically significant positive correlation was found between PFS and lower immune cell infiltrations in the intratumoral compartment (CD3+, CD4+, and CD11c+ cells), and increased numbers of immune cells in the extratumoral compartment were associated with longer PFS (CD3+, CD4+, CD8+, all expressing PD-1). Furthermore, the distribution of some immune cell subsets correlated with complete treatment response (PD-1/PD-L1-positive CD4+ and PD-1-positive CD8+ cells). Our results suggest that patients may have a better ILP outcome if the metastases exhibit a lower distribution of specific immune cell subtypes intratumorally and a higher extratumoral distribution of some immune cell subtypes.

The retinal pigment epithelium (RPE) is a specialised monolayer of pigmented epithelial cells in the outer retina. The extent to which RPE pigmentation is related to that of other tissues remains unclear. We utilised RPE thickness measured using optical coherence tomography (OCT) imaging as an indicator of RPE melanin content. UK Biobank data was used to assess the relationships between RPE thickness and fundus pigmentation, hair colour, skin colour and ability to tan. We performed a genome-wide association study (GWAS) to identify genetic loci associated with RPE thickness. We explored the genetic correlation between RPE thickness and pigmentation-related traits. We found that RPE thickness was not phenotypically or globally genetically correlated with hair colour, skin colour or ability to tan. Whilst RPE thickness was phenotypically correlated with fundus pigmentation, there was not significant global genetic correlation. Despite this, variants in key pigmentation loci including TYR and OCA2-HERC2 were significant in our GWAS of RPE thickness. We identified four genetic regions in which RPE thickness is locally genetically correlated with other pigmentation-related traits, all of which contain protein-coding genes that are central to melanogenesis and melanosome transport. Our study highlights shared and divergent features between RPE thickness and other pigmented traits.