Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 96
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
3.
Annu Rev Genomics Hum Genet ; 20: 41-72, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31100995

RESUMO

Human skin and hair color are visible traits that can vary dramatically within and across ethnic populations. The genetic makeup of these traits-including polymorphisms in the enzymes and signaling proteins involved in melanogenesis, and the vital role of ion transport mechanisms operating during the maturation and distribution of the melanosome-has provided new insights into the regulation of pigmentation. A large number of novel loci involved in the process have been recently discovered through four large-scale genome-wide association studies in Europeans, two large genetic studies of skin color in Africans, one study in Latin Americans, and functional testing in animal models. The responsible polymorphisms within these pigmentation genes appear at different population frequencies, can be used as ancestry-informative markers, and provide insight into the evolutionary selective forces that have acted to create this human diversity.

5.
Nat Commun ; 9(1): 4774, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429480

RESUMO

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

6.
Pigment Cell Melanoma Res ; 31(6): 728-735, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30281213

RESUMO

In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology. Significantly, this document encapsulates important advances in melanocyte and melanoma research including emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, epidemiology, pigment biophysics and chemistry, and evolution.

7.
BMJ Open ; 8(9): e025857, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232117

RESUMO

INTRODUCTION: Having many melanocytic naevi or 'moles' on the skin is the strongest predictor of melanoma; thus, much can be learnt from investigating naevi in the general population. We aim to improve the understanding of the epidemiology and biology of naevi by conducting a 3-year prospective study of melanocytic naevi in adults. METHODS AND ANALYSIS: This is a population-based cohort study of melanocytic naevi in 200 adults aged 20-69 years recruited via the Australian electoral roll. At baseline, participants will complete a questionnaire on their sun behaviour and health and undergo a clinical examination. Three-dimensional (3D) total-body photography will be used to record the images of skin lesions. Pigmented naevi will be analysed in terms of number, diameter, colour and border irregularity using automated analysis software (excluding scalp, beneath underwear and soles of feet). All naevi ≥5 mm will be recorded using the integrated dermoscopy photographic system. A saliva sample will be obtained at baseline for genomic DNA analysis of pigmentation, naevus and melanoma-associated genes using the Illumina HumanCoreExome platform. The sun behaviour and health follow-up questionnaire, clinical examination and 3D total-body photography will be repeated every 6 months for 3 years. The first 50 participants will also undergo manual counts of naevi ≥2 mm and ≥5 mm at baseline, 6-month and 12-month follow-ups. Microbiopsy and excision of naevi of research interest is planned to commence at the 18-month time point among those who agree to donate samples for detailed histopathological and molecular assessment. ETHICS AND DISSEMINATION: This study was approved by the Metro South Health Human Research Ethics Committee in April 2016 (approval number: HREC/16/QPAH/125). The findings will be disseminated through peer-reviewed and non-peer-reviewed publications and presentations at conferences.

8.
9.
Artigo em Inglês | MEDLINE | ID: mdl-29781575

RESUMO

The POU domain family of transcription factors play a central role in embryogenesis and are highly expressed in neural crest cells and the developing brain. BRN2 is a class III POU domain protein that is a key mediator of neuroendocrine and melanocytic development and differentiation. While BRN2 is a central regulator in numerous developmental programs, it has also emerged as a major player in the biology of tumourigenesis. In melanoma, BRN2 has been implicated as one of the master regulators of the acquisition of invasive behaviour within the phenotype switching model of progression. As a mediator of melanoma cell phenotype switching, it coordinates the transition to a dedifferentiated, slow cycling and highly motile cell type. Its inverse expression relationship with MITF is believed to mediate tumour progression and metastasis within this model. Recent evidence has now outlined a potential epigenetic switching mechanism in melanoma cells driven by BRN2 expression that induces melanoma cell invasion. We summarize the role of BRN2 in tumour cell dissemination and metastasis in melanoma, while also examining it as a potential metastatic regulator in other tumour models.

10.
Oncotarget ; 9(9): 8206-8222, 2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29492189

RESUMO

Besides somatic mutations or drug efflux, epigenetic reprogramming can lead to acquired drug resistance. We recently have identified early stress-induced multi-drug tolerant cancer cells termed induced drug-tolerant cells (IDTCs). Here, IDTCs were generated using different types of cancer cell lines; melanoma, lung, breast and colon cancer. A common loss of the H3K4me3 and H3K27me3 and gain of H3K9me3 mark was observed as a significant response to drug exposure or nutrient starvation in IDTCs. These epigenetic changes were reversible upon drug holidays. Microarray, qRT-PCR and protein expression data confirmed the up-regulation of histone methyltransferases (SETDB1 and SETDB2) which contribute to the accumulation of H3K9me3 concomitantly in the different cancer types. Genome-wide studies suggest that transcriptional repression of genes is due to concordant loss of H3K4me3 and regional increment of H3K9me3. Conversely, genome-wide CpG site-specific DNA methylation showed no common changes at the IDTC state. This suggests that distinct histone methylation patterns rather than DNA methylation are driving the transition from parental to IDTCs. In addition, silencing of SETDB1/2 reversed multi drug tolerance. Alterations of histone marks in early multi-drug tolerance with an increment in H3K9me3 and loss of H3K4me3/H3K27me3 is neither exclusive for any particular stress response nor cancer type specific but rather a generic response.

11.
Clin Cancer Res ; 24(12): 2901-2912, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29535131

RESUMO

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.

12.
J Invest Dermatol ; 138(7): 1636-1644, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29476775

RESUMO

The melanoma transformation rate of an individual nevus is very low despite the detection of oncogenic BRAF or NRAS mutations in 100% of nevi. Acquired melanocytic nevi do, however, mimic melanoma, and approximately 30% of all melanomas arise within pre-existing nevi. Using whole-exome sequencing of 30 matched nevi, adjacent normal skin, and saliva we sought to identify the underlying genetic mechanisms for nevus development. All nevi were clinically, dermoscopically, and histopathologically documented. In addition to identifying somatic mutations, we found mutational signatures relating to UVR mirroring those found in cutaneous melanoma. In nevi we frequently observed the presence of the UVR mutation signature compared with adjacent normal skin (97% vs. 10%, respectively). Copy number aberration analysis showed that for nevi with copy number loss of tumor suppressor genes, this loss was balanced by loss of potent oncogenes. Moreover, reticular and nonspecific patterned nevi showed an increased (P < 0.0001) number of copy number aberrations compared with globular nevi. The mutation signature data generated in this study confirms that UVR strongly contributes to nevogenesis. Copy number changes reflect at a genomic level the dermoscopic differences of acquired melanocytic nevi. Finally, we propose that the balanced loss of tumor suppressor genes and oncogenes is a protective mechanism of acquired melanocytic nevi.

13.
Pigment Cell Melanoma Res ; 31(4): 457-458, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29419941
14.
Pigment Cell Melanoma Res ; 31(1): 51-63, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28755520

RESUMO

A SNP within intron4 of the interferon regulatory factor4 (IRF4) gene, rs12203592*C/T, has been independently associated with pigmentation and age-specific effects on naevus count in European-derived populations. We have characterized the cis-regulatory activity of this intronic region and using human foreskin-derived melanoblast strains, we have explored the correlation between IRF4 rs12203592 homozygous C/C and T/T genotypes with TYR enzyme activity, supporting its association with pigmentation traits. Further, higher IRF4 protein levels directed by the rs12203592*C allele were associated with increased basal proliferation but decreased cell viability following UVR, an etiological factor in melanoma development. Since UVR, and accompanying IFNγ-mediated inflammatory response, is associated with melanomagenesis, we evaluated its effects in the context of IRF4 status. Manipulation of IRF4 levels followed by IFNγ treatment revealed a subset of chemokines and immuno-evasive molecules that are sensitive to IRF4 expression level and genotype including CTLA4 and PD-L1.

15.
PLoS One ; 12(10): e0186647, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29040338

RESUMO

Changes in dermoscopic patterns of naevi may be associated with melanoma; however, there is no consensus on which dermoscopic classification system is optimal. To determine whether different classification systems give comparable results and can be combined for analysis, we applied two systems to a case-control study of melanoma with 1037 participants: 573 classified using a "1/3 major feature" system, 464 classified based on rules of appearance, and 263 classified with both criteria. There was strong correlation for non-specific (Spearman R = 0.96) and reticular (Spearman R = 0.82) naevi, with a slight bias for globular naevi with the rules of appearance system. Inter-observer reliability was high for the rules of appearance system, particularly for reticular naevi (Pearson >0.97). We show that different classification systems for naevi can be combined for data analysis, and describe a method for determining what adjustments may need to be applied to combine data sets.


Assuntos
Dermoscopia/normas , Melanoma/classificação , Nevo Pigmentado/classificação , Neoplasias Cutâneas/classificação , Adulto , Análise de Variância , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/patologia , Pessoa de Meia-Idade , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patologia , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Terminologia como Assunto
16.
Mol Cancer Res ; 15(9): 1184-1196, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28607006

RESUMO

Exposure of melanocytes to ultraviolet radiation (UVR) induces the formation of UV lesions that can produce deleterious effects in genomic DNA. Encounters of replication forks with unrepaired UV lesions can lead to several complex phenomena, such as the formation of DNA double-strand breaks (DSBs). The NR4A family of nuclear receptors are transcription factors that have been associated with mediating DNA repair functions downstream of the MC1R signaling pathway in melanocytes. In particular, emerging evidence shows that upon DNA damage, the NR4A2 receptor can translocate to sites of UV lesion by mechanisms requiring post-translational modifications within the N-terminal domain and at a serine residue in the DNA-binding domain at position 337. Following this, NR4A2 aids in DNA repair by facilitating chromatin relaxation, allowing accessibility for DNA repair machinery. Using A2058 and HT144 melanoma cells engineered to stably express wild-type or mutant forms of the NR4A2 proteins, we reveal that the expression of functional NR4A2 is associated with elevated cytoprotection against UVR. Conversely, knockdown of NR4A2 expression by siRNA results in a significant loss of cell viability after UV insult. By analyzing the kinetics of the ensuing 53BP1 and RAD51 foci following UV irradiation, we also reveal that the expression of mutant NR4A2 isoforms, lacking the ability to translocate, transactivate, or undergo phosphorylation, display compromised repair capacity.Implications: These data expand the understanding of the mechanism by which the NR4A2 nuclear receptor can facilitate DNA DSB repair. Mol Cancer Res; 15(9); 1184-96. ©2017 AACR.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , DNA de Neoplasias/efeitos da radiação , Melanoma/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Humanos , Melanócitos/metabolismo , Melanócitos/efeitos da radiação , Melanoma/metabolismo , Melanoma/patologia , Melanoma/radioterapia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Transfecção , Raios Ultravioleta
17.
Dermatology ; 233(1): 1-15, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28463841

RESUMO

Human pigmentation characteristics play an important role in the effects of sun exposure, skin cancer induction and disease outcomes. Several of the genes most important for this diversity are involved in the regulation and distribution of melanin pigmentation or enzymes involved in melanogenesis itself within the melanocyte cell present in the skin, hair and eyes. The single nucleotide polymorphisms and extended haplotypes within or surrounding these genes have been identified as risk factors for skin cancer, in particular, melanoma. These same polymorphisms have been under selective pressure leading towards lighter pigmentation in Europeans in the last 5,000-20,000 years that have driven the increase in frequency in modern populations. Although pigmentation is a polygenic trait, due to interactive and quantitative gene effects, strong phenotypic associations are readily apparent for these major genes. However, predictive value and utility are increased when considering gene polymorphism interactions. In melanoma, an increased penetrance is found in cases when pigmentation gene risk alleles such as MC1R variants are coincident with mutation of higher-risk melanoma genes including CDKN2A, CDK4 and MITF E318K, demonstrating an interface between the pathways for pigmentation, naevogenesis and melanoma. The clinical phenotypes associated with germline changes in pigmentation and naevogenic genes must be understood by clinicians, and will be of increasing relevance to dermatologists, as genomics is incorporated into the delivery of personalised medicine.


Assuntos
Albinismo/genética , Melanoma/genética , Nevo/genética , Neoplasias Cutâneas/genética , Pigmentação da Pele/genética , Proteína Agouti Sinalizadora/genética , Antígenos de Neoplasias/genética , Antiporters/genética , Evolução Biológica , Quinase 4 Dependente de Ciclina/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Fosfolipases A2 do Grupo VI/genética , Cor de Cabelo/genética , Humanos , Fatores Reguladores de Interferon/genética , Oxirredutases Intramoleculares/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Fator de Transcrição Associado à Microftalmia/genética , Monofenol Mono-Oxigenase/genética , Oxirredutases/genética , Polimorfismo de Nucleotídeo Único , Purina-Núcleosídeo Fosforilase/genética , Receptor Tipo 1 de Melanocortina/genética , Fator de Células-Tronco/genética
18.
J Invest Dermatol ; 137(9): 1887-1894, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28502801

RESUMO

Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait at genome-wide significance (P = 4.1 × 10-9); to our knowledge this is previously unreported. We also confirm previously identified loci, rs12203592 near IRF4 (P = 8.8 × 10-13) and rs4268748 near MC1R (P = 1.2 × 10-15). At all three loci we highlight putative functionally relevant SNPs. There are a number of red hair/low pigmentation alleles of MC1R; we found that together these MC1R alleles explained 4.1% of variance in skin pattern damage. We also show that skin aging and reported experience of sunburns was proportional to the degree of penetrance for red hair of alleles of MC1R. Our work has uncovered genetic contributions to skin aging and confirmed previous findings, showing that pigmentation is a critical determinant of skin aging.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores Reguladores de Interferon/genética , Envelhecimento da Pele/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valores de Referência , Papel (figurativo) , Pigmentação da Pele/genética
19.
Arch Dermatol Res ; 309(4): 305-310, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28255674

RESUMO

Skin biopsies are a valuable technique in the diagnosis of cutaneous inflammatory and neoplastic conditions. We were interested to test the minimal size or equivalent volume by dilution of proteolytically disassociated skin tissue required to allow the isolation and propagation of cutaneous cells, for freezing, storage and biochemical analysis. It was possible to propagate with 100% efficiency fibroblast and melanocytic cells from a 0.1 to 0.5 mm3 equivalent neonatal foreskin sample using a combination of DispaseII and CollagenaseIV. The smallest tissue dilution that allowed melanocytic cell culture was 0.01 mm3, which equated to approximately 16 cells based on the average skin density of melanocytes. However, passaging of cells to create frozen stocks was achieved routinely only from 1 mm3 skin, equating to 1560 cells. Tissue-specific antigen expression of these cultures was tested by western blot of total protein extracts. There was no pigmentation antigen expression in fibroblast cultures; however, smooth muscle actin protein expression was high in fibroblast but absent from melanocytic cell strains. Melanocytic cells expressed pigmentation antigens and E-cadherin, but these were not detected in fibroblasts. Moreover, maturation of these melanocytic cells resulted in a decrease of Dopachrome Tautomerase antigen expression and induction of Tyrosinase protein consistent with the differentiation potential seen in cell cultures derived routinely from large sections of skin tissue.


Assuntos
Técnicas de Cultura de Células/métodos , Fibroblastos/fisiologia , Melanócitos/fisiologia , Pele/citologia , Caderinas/metabolismo , Diferenciação Celular , Células Cultivadas , Criopreservação , Humanos , Oxirredutases Intramoleculares/metabolismo , Miniaturização , Monofenol Mono-Oxigenase/metabolismo , Pele/metabolismo , Pigmentação da Pele
20.
EBioMedicine ; 16: 63-75, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28119061

RESUMO

While invasion and metastasis of tumour cells are the principle factor responsible for cancer related deaths, the mechanisms governing the process remain poorly defined. Moreover, phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. In the context of melanoma, heterogeneity between two transcription factors, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. Here we report the identification of the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis.


Assuntos
Movimento Celular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteínas de Homeodomínio/genética , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Fatores de Transcrição NFI/genética , Fatores do Domínio POU/genética , Animais , Western Blotting , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Melanoma/metabolismo , Melanoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fator de Transcrição Associado à Microftalmia/metabolismo , Microscopia de Fluorescência , Fatores de Transcrição NFI/metabolismo , Invasividade Neoplásica , Fatores do Domínio POU/metabolismo , Ligação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA