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Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. Teaser: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.
RESUMEN
The nonprofit organization International Dermatology Outcome Measures (IDEOM) is committed to improving the implementation of patient-centered outcome measures in dermatologic disease. At a conference adjacent to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting, the IDEOM Psoriatic Disease Workgroup presented updates on recent efforts in outcome measure advancement. Dr. Alice Gottlieb presented the preliminary findings of a study within the Mount Sinai Health System that aims to determine how well the IDEOM musculoskeletal (MSK) symptom framework, which uses the Psoriasis Epidemiology Screening Tool (PEST) and the Psoriatic Arthritis Impact of Disease (PsAID) instruments, functions in clinical settings. Drs. Joseph Merola and Lourdes Perez-Chada updated attendees on the IDEOM MSK-Q, a 9-item patient-reported questionnaire designed to measure the intensity and impact of MSK symptoms on the quality of life in patients with psoriasis (PsO) with or without psoriatic arthritis (PsA). Dr. Vibeke Strand summarized the Outcome Measures in Rheumatology (OMERACT) 2023 conference sessions. Dr. April Armstrong discussed the preliminary findings of a multicentered study designed to validate the 7-item Dermatology Treatment Satisfaction Instrument (DermSat-7) among patients with PsO. She also introduced the Psoriasis and Psoriatic Arthritis Treatment Satisfaction Instrument, a tool that seeks to capture the level of patient satisfaction with current therapy for PsO and PsA. This report summarizes the developments discussed at the IDEOM PsO and PsA research workgroups during the GRAPPA 2023 annual meeting.
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Despite substantial evidence that methotrexate (MTX) has inferior efficacy, safety, and tolerability compared to newer systemic therapies, MTX remains one of the most commonly prescribed first-line systemic therapies for psoriatic arthritis worldwide and for psoriasis in some countries. At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting in Dublin, Ireland, Drs. William Tillett and Joseph Merola engaged in debate over whether MTX should be the first systemic therapy used in psoriatic disease (PsD). Each presented evidence-based arguments, incorporating multiple data sources, including clinical trials, in support for and against MTX's status as first-line systemic therapy for PsD. This article summarizes their debate for the broader PsD community.
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During the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting, the International Dermatology Outcome Measures (IDEOM) psoriatic disease (PsD) workgroup presented an update on their efforts toward measurement of musculoskeletal (MSK) symptoms in patients with PsD. Dr. Joseph Merola initiated the presentation emphasizing the vital importance of assessing MSK symptoms in patients with psoriasis (PsO) regardless of whether they have been diagnosed with psoriatic arthritis (PsA). He also discussed existing challenges for evaluating MSK symptoms in patients with PsO without a PsA diagnosis. Dr. Lourdes Perez-Chada then presented their work on the development and validation of the IDEOM Musculoskeletal Questionnaire (MSK-Q), a patient-reported questionnaire developed by the IDEOM to capture the intensity and impact of MSK symptoms on quality of life in patients with PsO with or without PsA. Dr. Perez-Chada also introduced a set of ongoing studies employing the IDEOM MSK-Q, highlighting the potential effects of the data collected through this innovative tool.
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Although discussed using variable terminology, cutaneous BRCA1-associated protein (BAP1)-inactivated melanocytic tumor (BIMT) has been considered a discrete diagnostic entity since 2011. Here, we review the initial genomic studies that identified these distinct melanocytic tumors and the clinical and histopathological features that define these tumors. These epithelioid, predominantly dermal, and melanocytic tumors present as erythematous nodules and histopathologically have features that may overlap with Spitz nevi and nevoid melanoma. There is no sex predilection, and cutaneous BIMTs can appear at any age; however, in most familial (germline mutant) cases patients have multiple cutaneous tumors with a first diagnosis in the second or third decade of life; ocular melanoma and other tumors are increasingly identified in these kindreds with germline BAP1 mutation. These tumors have been described with a myriad of terms including: Wiesner nevus, nevoid melanoma-like melanocytic proliferation (NEMMP), BAP1 mutant Spitz nevus, BAP1 mutant nevoid melanoma, cutaneous BAPoma, and most recently cutaneous BIMT.
Asunto(s)
Proteína BRCA1/metabolismo , Neoplasias del Ojo/genética , Melanocitos/patología , Melanoma/genética , Nevo de Células Epitelioides y Fusiformes/genética , Neoplasias Cutáneas/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Proliferación Celular , Neoplasias del Ojo/patología , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Humanos , Masculino , Melanoma/patología , Nevo de Células Epitelioides y Fusiformes/patología , Piel/patología , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
Psoriatic arthritis is a common form of inflammatory arthritis that frequently accompanies psoriasis of the skin-up to 30% of patients with psoriasis are affected. Recognition of the clinical features of psoriatic arthritis is critical, as delayed detection and untreated disease may result in irreparable joint injury, impaired physical function, and a significantly reduced quality of life. Recent epidemiologic studies have also supported that psoriatic arthritis is associated with cardiometabolic and cerebrovascular comorbidities, including coronary heart disease, diabetes mellitus, hypertension, dyslipidemia, and cerebrovascular accidents, further highlighting the importance of identifying affected patients. Dermatologists are poised for the early detection of psoriatic arthritis, as psoriasis predates its development in as many as 80% of patients. In an effort to further acquaint dermatologists and other clinicians with psoriatic arthritis, this review provides a detailed overview, emphasizing its salient clinical features, and discusses classification criteria, validated screening tools, and simple musculoskeletal examination maneuvers that may facilitate earlier detection and treatment of the disorder.