Pigment Cell & Melanoma Research最新文献

Repigmentation is an essential outcome in vitiligo assessment, yet it remains broadly defined. While perspectives from vitiligo experts have been explored, gaining insights from patients is crucial for a more comprehensive understanding. Ultimately, this could contribute to the development and refinement of core outcome sets for vitiligo. This study aimed to determine aspects of repigmentation patients consider most important. Two surveys and one focus group were conducted, involving 34 patients/patient caregivers and 20 patient representatives. In the surveys, aspects were deemed important if ≥ 70% of participants rated them as such. The focus group used the nominal group technique to rank the five most important self-suggested aspects. The survey results indicate reduction of target lesion surface area, maintenance of repigmentation, and cessation of spread as important. The focus group identified additional aspects, including “time to repigment,” “location of lesions,” and “color match”. This study identified key aspects of repigmentation important to vitiligo patients. While survey results in general aligned with the core domain set for vitiligo clinical trials, the focus group highlighted additional factors. Incorporating these patient-centered priorities into future core outcome sets could enhance the clinical relevance of vitiligo research and ensure outcomes reflect patient perspectives.

Tumor-mutational burden (TMB) is a mechanistic surrogate of neo-antigen load and thus a plausible biomarker for response to immune checkpoint blockade (ICB). In melanoma, however, the extreme right tail of the mutational spectrum, known as “hypermutation,” remains poorly characterized. This study sought to explore an a priori threshold of hypermutation that would delineate a subgroup with extraordinary benefit from ICB therapy. This study analyzed individual-patient data from independent cohorts comprising 710 ICB-treated melanoma patients profiled by whole-exome sequencing or FDA-approved targeted panels. Hypermutated tumors displayed a striking enrichment for higher objective response and complete response (CR) rates (p < 0.0001). Hypermutation independently predicted prolonged progression-free survival and overall survival. By contrast, the conventional ≥ 10 mut/Mb cut-off captured many treatment-eligible patients but conferred markedly lower CR enrichment and weaker survival discrimination. A super-high TMB threshold of ≥ 25 mut/Mb by MSK-IMPACT identifies a distinct subset of melanoma patients who achieve truly exceptional benefit, with nearly one in two attaining clinical cure following ICB therapy. These data support prospective validation of “hypermutation” as a clinically actionable biomarker, refine patient counseling, and inform trial stratification in the era of personalized cancer immunotherapy.

The tripartite motif (TRIM) family of E3 ubiquitin ligases is known to play a crucial role in the initiation, growth, and metastasis of various tumors. However, little is known about the biological features and relevant molecular mechanism of Tripartite motif-containing 63 (TRIM 63) in melanoma. The expression levels of TRIM63 and purinergic receptor P2Y1 (P2RY1) in melanoma were examined by online database. Cell counting kit-8 (CCK-8) and colony formation assay were carried out to explore the effects of TRIM63 on melanoma cells proliferation. Transwell assay was used to explore the influence of TRIM63 on melanoma cells invasion and migration. Bioinformatics, co-immunoprecipitation (co-IP) assay, ubiquitination assay, and protein stability assay were used to detect the regulatory mechanism of TRIM63 on P2RY1. TRIM63 was upregulated in melanoma samples, and a higher expression level of TRIM63 indicated a shorter overall survival of melanoma patients. Knocked down of TRIM63 obviously suppressed the proliferation, invasion, and migration abilities of melanoma cells. Mechanistically, TRIM63 was regarded as a posttranslational mediator of P2RY1, and TRIM63 was co-immunoprecipitated with P2RY1 and degraded its protein level. Notably, silencing P2RY1 alleviated melanoma cells progression by TRIM63 depletion. Collectively, these data suggested that TRIM63 contributed to melanoma cells growth and mobility by ubiquitination of P2RY1 and may be a promising candidate as a potential diagnostic and therapeutic marker for patients with melanoma.

Oculocutaneous albinism type 1 (OCA1) caused by pathogenic variants of the TYR gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in skin, hair, and eyes. We had the opportunity to examine five East Cameroon Baka rainforest hunter-gatherers (historically called “Pygmies”) with albinism and belonging to three different families. Screening of known albinism genes revealed a homozygous missense variant in the TYR gene, NM_000372.5: c.1109T>C; p.Met370Thr. In addition, one patient was also hemizygous for a variant in GPR143, the gene involved in ocular albinism (OA1). Another patient was also heterozygous for the common African and Afro-American 2.7-kb deletion in the OCA2 gene indicating admixture of one parent with neighboring Nzimé Bantu-speaking farmers. This is the first report of the occurrence of OCA1 in African rainforest hunter-gatherers.

Shank color in chickens is a classic quantitative trait governed by four genetic loci. Among these, the Inhibition of dermal melanin (ID) locus, which suppresses dermal melanogenesis in the shank, is the sole sex-linked mutation and its molecular mechanisms remain elusive. To identify the causal mutation, we established a resource population segregating for shank colors. A genome-wide association study utilizing FarmCPU software identified a top-associated SNP on the Z chromosome. Linkage mapping subsequently narrowed the candidate region, within which we discovered a candidate structural variant associated with the yellow shank phenotype. This variant is characterized by a 143 bp deletion coupled with a 2 bp insertion. CDKN2A was the only gene within the same topologically associating domain to exhibit differential expression. Functional validation via CRISPR/Cas9-edited cells demonstrated that this mutation regulates CDKN2A transcription and is responsible for the ID shank color in chickens. We propose that the resulting absence of melanocytes is likely due to apoptosis. This work resolves the molecular basis of the ID locus, thereby completing the genetic puzzle of chicken shank color. This discovery enables the development of molecular markers for auto-sexing of day-old chicks, a tool with significant potential for the poultry industry.

Giant congenital melanocytic nevi (GCMN) are benign mosaic disorders that may give rise to various tumor types through incompletely understood mechanisms. We characterized a series of two melanomas and four mesenchymal tumors (two embryonal rhabdomyosarcomas, one small round cell sarcoma, one low-grade mesenchymal tumor) arising in GCMN. Median onset age was 3.5 years and 3 months for melanoma and mesenchymal tumor patients, respectively. Both melanoma patients succumbed within 27 months from diagnosis, whereas no patients progressed in the mesenchymal group (median follow-up 46 months). NRAS Q61, BRAF V600E mutation, and a novel in frame BIN1::BRAF fusion were detected in four, one, and one cases, respectively, with a higher variant allele frequency in the tumors compared with the matched GCMN. Copy number alterations and/or copy-neutral loss of heterozygosity were exclusively found in the tumors in all cases. An inactivating ASXL1 variant and an in-frame KDM5B::LPGAT1 fusion were identified in one melanoma; paternal disomy of 11p15.5 in both embryonal rhabdomyosarcomas. Mesenchymal tumors and melanomas showed distinct transcriptional profiles enriched in muscle and synapse organization and epidermal differentiation genes, respectively.