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1.
Pigment Cell Melanoma Res ; 35(3): 369-386, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35229492

RESUMEN

Acral melanoma (AM) tumors arise on the palms, soles, fingers, toes, and nailbeds. A comprehensive systematic meta-analysis of AM genomic aberrations has not been conducted to date. A literature review was carried out to identify studies sequencing AM. Whole-genome/exome data from 181 samples were identified. Targeted panel sequencing data from MSK-IMPACT were included as a validation cohort (n = 92), and studies using targeted hot spot sequencing were also collated for BRAF (n = 26 studies), NRAS (n = 21), and KIT (n = 32). Statistical analysis indicated BRAF, NRAS, PTEN, TYRP1, and KIT as significantly mutated genes. Frequent copy-number aberrations were also found for important cancer genes, such as CDKN2A, KIT, MDM2, CCND1, CDK4, and PAK1, among others. Mapping genomic alterations within the context of the hallmarks of cancer identified four components frequently altered, including (i) sustained proliferative signaling and (ii) evading growth suppression, (iii) genome instability and mutation, and (iv) enabling replicative immortality. This analysis provides the largest analysis of genomic aberrations in AM in the literature to date and highlights pathways that may be therapeutically targetable.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Genómica , Humanos , Melanoma/patología , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/patología , Melanoma Cutáneo Maligno
2.
J Thorac Oncol ; 17(7): 873-889, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35462085

RESUMEN

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.


Asunto(s)
Neoplasias Pulmonares , Melanoma , Mesotelioma Maligno , Mesotelioma , Neoplasias Cutáneas , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Melanoma/genética , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/cirugía , Calidad de Vida , Neoplasias Cutáneas/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo
3.
JCO Clin Cancer Inform ; 5: 143-154, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33513031

RESUMEN

PURPOSE: Pathogenic BAP1 germline variants cause a tumor-predisposition syndrome (BAP1-TPDS) linked to uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma. Surveillance of carriers of pathogenic BAP1 variants provides an opportunity for early tumor detection; however, there are no evidence-based guidelines for management of BAP1-TPDS, nor health economic evaluation; this study aims to provide this evidence. METHODS: We created a Markov microsimulation health state transition model of BAP1 germline carriers to predict if active surveillance for the four main tumors influences survival and improves associated economic costs with a time horizon of 100 years from the perspective of the healthcare system (N = 10,000). Model inputs were derived from data published by the BAP1 Interest Group Consortium and other studies. Management and healthcare costs were extracted from Australian costing schedules (final figures converted to US dollars [USD]), and outcomes compared for individuals receiving surveillance with those in a nonsurveillance arm. Robustness was evaluated on 10,000 iterations of a 100-sample random sampling of the model output. RESULTS: On average, surveillance of BAP1 carriers increased survival by 4.9 years at an additional cost of $6,197 USD for the healthcare system including surveillance costs ($1,265 USD per life year gained). The nonsurveillance arm had more diagnosed late tumors (62.8% v 10.7%) and a higher rate of BAP1-related deaths (50.2% v 35.4%; a 29.5% increase). The model was cost-effective under all sensitivity analyses. Our secondary robustness analysis estimated that 99.86% of 100-sample iterations were cost-effective and 19.67% of these were cost-saving. CONCLUSION: It is recommended that carriers of BAP1 germline variants are identified and undertake active surveillance, as this model suggests that this could improve survival and be cost-effective for the healthcare system.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Proteínas Supresoras de Tumor , Ubiquitina Tiolesterasa , Australia , Análisis Costo-Beneficio , Mutación de Línea Germinal , Humanos , Melanoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética
4.
JMIR Dermatol ; 4(1): e24653, 2021 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-37632801

RESUMEN

BACKGROUND: Photography using a UV transmitting filter allows UV light to pass and can be used to illuminate UV blocking lotions such as sunscreens. OBJECTIVE: The aim of this study is to compare currently available UV photography cameras and assess whether these devices can be used as visualization tools for adequate coverage of sun protection lotions. METHODS: This study was conducted in 3 parts: in phase 1, 3 different UV cameras were tested; in phase 2, we explored whether UV photography could work on a range of sun protection products; and in phase 3, a UV webcam was developed and was field-tested in a beach setting. In phase 1, volunteers were recruited, and researchers applied 3 sun protection products (ranging from sun protection factor [SPF] 15 to 50+) to the participants' faces and arms. UV photography was performed using 3 UV cameras, and the subsequent images were compared. In phase 2, volunteers were recruited and asked to apply their own SPF products to their faces in their usual manner. UV photographs were collected in the morning and afternoon to assess whether the coverage remained over time. Qualitative interviews were conducted to assess the participants' level of satisfaction with the UV image. In phase 3, a small portable UV webcam was designed using a plug-and-play approach to enable the viewing of UV images on a larger screen. The developed webcam was deployed at a public beach setting for use by the public for 7 days. RESULTS: The 3 UV camera systems tested during phase 1 identified the application of a range of sun protection lotions of SPF 15 to 50+. The sensitivity of the UV camera devices was shown to be adequate, with SPF-containing products applied at concentrations of 2 and 1 mg/cm2 clearly visible and SPF-containing products applied at a concentration of 0.4 mg/cm2 having lower levels of coverage. Participants in phase 2 reported high satisfaction with the UV photography images, with 83% (29/35) of participants likely to use UV photography in the future. During phase 2, it was noted that many participants used tinted SPF-containing cosmetics, and several tinted products were further tested. However, it was observed that UV photography could not identify the areas missed for all tinted products. During phase 3, the electrical components of the UV webcam remained operational, and the camera was used 233 times by the public during field-testing. CONCLUSIONS: In this study, we found that UV photography could identify the areas missed by sun protection lotions with chemical filters, and participants were engaged with personalized feedback. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000975190; http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377089 ; Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12619000145101; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376672.

5.
Mol Cancer Res ; 19(6): 991-1004, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33707307

RESUMEN

Mucosal melanoma is a rare subtype of melanoma. To date, there has been no comprehensive systematic collation and statistical analysis of the aberrations and aggregated frequency of driver events across multiple studies. Published studies using whole genome, whole exome, targeted gene panel, or individual gene sequencing were identified. Datasets from these studies were collated to summarize mutations, structural variants, and regions of copy-number alteration. Studies using next-generation sequencing were divided into the "main" cohort (n = 173; fresh-frozen samples), "validation" cohort (n = 48; formalin-fixed, paraffin-embedded samples) and a second "validation" cohort comprised 104 tumors sequenced using a targeted panel. Studies assessing mutations in BRAF, KIT, and NRAS were summarized to assess hotspot mutations. Statistical analysis of the main cohort variant data revealed KIT, NF1, BRAF, NRAS, SF3B1, and SPRED1 as significantly mutated genes. ATRX and SF3B1 mutations occurred more commonly in lower anatomy melanomas and CTNNB1 in the upper anatomy. NF1, PTEN, CDKN2A, SPRED1, ATM, CHEK2, and ARID1B were commonly affected by chromosomal copy loss, while TERT, KIT, BRAF, YAP1, CDK4, CCND1, GAB2, MDM2, SKP2, and MITF were commonly amplified. Further notable genomic alterations occurring at lower frequencies indicated commonality of signaling networks in tumorigenesis, including MAPK, PI3K, Notch, Wnt/ß-catenin, cell cycle, DNA repair, and telomere maintenance pathways. This analysis identified genomic aberrations that provide some insight to the way in which specific pathways may be disrupted. IMPLICATIONS: Our analysis has shown that mucosal melanomas have a diverse range of genomic alterations in several biological pathways. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/6/991/F1.large.jpg.


Asunto(s)
Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN , Genómica/métodos , Melanoma/genética , Mutación , Neoplasias Cutáneas/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Melanoma/patología , Transducción de Señal/genética , Neoplasias Cutáneas/patología , Secuenciación Completa del Genoma/métodos
6.
Mol Oncol ; 13(7): 1503-1518, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31044505

RESUMEN

Drugs such as gemcitabine that increase replication stress are effective chemotherapeutics in a range of cancer settings. These drugs effectively block replication and promote DNA damage, triggering a cell cycle checkpoint response through the ATR-CHK1 pathway. Inhibiting this signalling pathway sensitises cells to killing by replication stress-inducing drugs. Here, we investigated the effect of low-level replication stress induced by low concentrations (> 0.2 mm) of the reversible ribonucleotide reductase inhibitor hydroxyurea (HU), which slows S-phase progression but has little effect on cell viability or proliferation. We demonstrate that HU effectively synergises with CHK1, but not ATR inhibition, in > 70% of melanoma and non-small-cell lung cancer cells assessed, resulting in apoptosis and complete loss of proliferative potential in vitro and in vivo. Normal fibroblasts and haemopoietic cells retain viability and proliferative potential following exposure to CHK1 inhibitor plus low doses of HU, but normal cells exposed to CHK1 inhibitor combined with submicromolar concentrations of gemcitabine exhibited complete loss of proliferative potential. The effects of gemcitabine on normal tissue correlate with irreversible ATR-CHK1 pathway activation, whereas low doses of HU reversibly activate CHK1 independently of ATR. The combined use of CHK1 inhibitor and subclinical HU also triggered an inflammatory response involving the recruitment of macrophages in vivo. These data indicate that combining CHK1 inhibitor with subclinical HU is superior to combination with gemcitabine, as it provides equal anticancer efficacy but with reduced normal tissue toxicity. These data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Hidroxiurea/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Desoxicitidina/efectos adversos , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Femenino , Humanos , Hidroxiurea/efectos adversos , Hidroxiurea/uso terapéutico , Neoplasias Pulmonares/patología , Melanoma/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Gemcitabina
7.
Clin Cancer Res ; 24(12): 2901-2912, 2018 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-29535131

RESUMEN

Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo Here, we have investigated the molecular basis of this activity.Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines.Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumor growth in vivo In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S-phase cell-cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumors appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i.Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumors, and may be a useful marker of replication stress in vivoClin Cancer Res; 24(12); 2901-12. ©2018 AACR.


Asunto(s)
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Replicación del ADN/efectos de los fármacos , Resistencia a Antineoplásicos , Melanoma/genética , Melanoma/metabolismo , Estrés Fisiológico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Mitosis/efectos de los fármacos , Mitosis/genética , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Estrés Fisiológico/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
8.
J Natl Cancer Inst ; 110(12): 1328-1341, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30517737

RESUMEN

Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/diagnóstico , Síndromes Neoplásicos Hereditarios/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Edad de Inicio , Alelos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Síndromes Neoplásicos Hereditarios/epidemiología , Fenotipo , Medición de Riesgo
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