Pigment Cell & Melanoma Research最新文献

This study reports co-segregation of a pathogenic CDKN2A variant with both melanoma and breast cancer in a four-generation pedigree. Eighteen individuals were test positive (n = 10), obligate (n = 5) or assumed carriers (n = 3) of the CDKN2A variant. Eleven of these had multiple melanomas, with initial diagnoses from teens to fifties. Six of thirteen female carriers had breast cancer (n = 5 test positive, n = 1 assumed carrier), with diagnoses ranging from thirties to sixties. Additional cancer diagnoses included pancreatic, and head and neck cancers. This study illustrates a possible genotype–phenotype association between a pathogenic CDKN2A variant and the co-occurrence of melanoma and breast cancer in a hereditary context.

Since its discovery more than a quarter century ago, PTEN has emerged as one of the most potent tumor suppressors and its loss of function is common to numerous cancer types including glioblastoma, prostate cancer, small cell lung cancer, and melanoma. PTEN is a lipid and protein phosphatase that contributes to various cellular processes, primarily by regulating key signaling pathways. Extensive research over the past two decades has uncovered many aspects of PTEN regulation and function and highlighted the role of PTEN in tumor suppression. PTEN loss-of-function is associated with the progression of a substantial portion of melanoma cases, and while its role in melanoma suppression is often ascribed to its inhibition of the PI3K/AKT signaling pathway, recent studies may hint at a more complex role for PTEN in melanoma. In this review, we provide an overview of how PTEN suppresses melanomagenesis.

The melanocortin-1-receptor (MC1R) has a key role in melanocyte pigmentation regulation. Certain MC1R germline genetic variants (R alleles) result in deficient melanin production and are associated with red hair, freckling, UV sensitivity, and melanoma susceptibility. We aimed to address whether inherited polymorphisms in MC1R impact the efficacy of immune checkpoint inhibitors (ICI) in patients with metastatic melanoma. Patients with advanced melanoma undergoing ICI treatment were genotyped for MC1R variants. The patients were grouped by their germline MC1R R variants (≥ 1 or 0) and followed for treatment response, progression-free survival (PFS) and overall survival (OS). Of the 103 patients included, 39 (37.9%) had at least one MC1R R allele (MC1R-R-carriers), whereas 64 patients did not harbor any R allele (MC1R-R-non-carriers). The hazard ratio (HR) for PFS in MC1R-R-carriers was 0.60, (95% CI 0.37–0.98, p = 0.043). The HR for OS was 0.63 (95% CI 0.37–1.08, p = 0.091). While MC1R is closely associated with melanoma susceptibility, its impact on ICI efficacy has not been explored previously. MC1R-R-carriers with metastatic melanoma had improved PFS when treated with ICIs. If validated in larger cohorts, MC1R genotyping may serve as a factor helping to predict response to ICIs in melanoma patients.

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.