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1.
Despina Handolias Renato Salemi William Murray Angela Tan Wendy Liu Amaya Viros Alexander Dobrovic John Kelly Grant A. McArthur 《Pigment cell & melanoma research》2010,23(2):210-215
In melanoma, mutations in KIT are most frequent in acral and mucosal subtypes and rarely reported in cutaneous melanomas particularly those associated with intermittent UV exposure. Conversely melanomas arising within chronic sun damaged skin are considered to harbour KIT mutations at higher rates. To characterize the frequency of KIT mutations in a representative melanoma population, 261 patients from two Australian melanoma centres were prospectively screened for mutations in exons 11, 13 and 17 of the KIT gene. A total of 257 patients had cutaneous melanoma arising from non-acral sites and four were acral melanomas. No mucosal or ocular melanomas were analysed. KIT mutations were identified in five tumours (2% of the entire cohort) including two acral melanomas. Two of the three non-acral melanomas with KIT mutations were associated with markers of chronic sun damage as assessed by the degree of skin elastosis. In the remaining cohort, 43% had chronically sun damaged skin. This report confirms that within an Australian population, KIT mutations are infrequent in cutaneous melanomas associated with both intermittent and chronic sun exposed skin. 相似文献
2.
Jamie Sheren Siriwimon Saichaemchan Witthawat Ariyawutyakorn Izabela Avolio Ethan Cabral Magdelena Glogowska Carol Amato Steven Robinson Jennifer Hintzsche Allison Applegate Eric Seelenfreund Rita Gonzalez Keith Wells Stacey Bagby John Tentler Aik‐Choon Tan Joshua Wisell Marileila Varella‐Garcia William Robinson 《Pigment cell & melanoma research》2017,30(1):53-62
Genomic rearrangements resulting in activating kinase fusions have been increasingly described in a number of cancers including malignant melanoma, but their frequency in specific melanoma subtypes has not been reported. We used break‐apart fluorescence in situ hybridization (FISH) to identify genomic rearrangements in tissues from 59 patients with various types of malignant melanoma including acral lentiginous, mucosal, superficial spreading, and nodular. We identified four genomic rearrangements involving the genes BRAF, RET, and ROS1. Of these, three were confirmed by Immunohistochemistry (IHC) or sequencing and one was found to be an ARMC10‐BRAF fusion that has not been previously reported in melanoma. These fusions occurred in different subtypes of melanoma but all in tumors lacking known driver mutations. Our data suggest gene fusions are more common than previously thought and should be further explored particularly in melanomas lacking known driver mutations. 相似文献
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Ana M. Arance Marcelo Sánchez Gemma Tell‐Marti Miriam Potrony Carles Conill Remco van Doorn Stefan Dentro Nelleke A. Gruis Pippa Corrie Vivek Iyer Carla Daniela Robles‐Espinoza Joan A. Puig‐Butille David J. Adams 《Pigment cell & melanoma research》2017,30(3):307-316
Melanoma in young children is rare; however, its incidence in adolescents and young adults is rising. We describe the clinical course of a 15‐year‐old female diagnosed with AJCC stage IB non‐ulcerated primary melanoma, who died from metastatic disease 4 years after diagnosis despite three lines of modern systemic therapy. We also present the complete genomic profile of her tumour and compare this to a further series of 13 adolescent melanomas and 275 adult cutaneous melanomas. A somatic BRAFV600E mutation and a high mutational load equivalent to that found in adult melanoma and composed primarily of C>T mutations were observed. A germline genomic analysis alongside a series of 23 children and adolescents with melanoma revealed no mutations in known germline melanoma‐predisposing genes. Adolescent melanomas appear to have genomes that are as complex as those arising in adulthood and their clinical course can, as with adults, be unpredictable. 相似文献
6.
The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark’s multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking ‘field melanocytes’, which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma. 相似文献
7.
Melanoma is the deadliest form of skin cancer, possessing a diverse landscape of subtypes with distinct molecular signatures and levels of aggressiveness. Although immense progress has been achieved therapeutically for patients with the most common forms of this disease, little is known of how to effectively treat patients with rarer subtypes of melanoma. These subtypes include acral lentiginous (the rarest form of cutaneous melanoma; AL), uveal, and mucosal melanomas, which display variations in distribution across (a) the world, (b) patient age‐groups, and (c) anatomic sites. Unfortunately, patients with these relatively rare subtypes of melanoma typically respond worse to therapies approved for the more common, non‐AL cutaneous melanoma and do not have effective alternatives, and thus consequently have worse overall survival rates. Achieving durable therapeutic responses in these high‐risk melanoma subtypes represents one of the greatest challenges of the field. This review aims to collate and highlight effective preclinical and/or clinical strategies against these rare forms of melanoma. 相似文献
8.
Victoria J. Mar Stephen Q. Wong Aleksandra Logan Trung Nguyen Jonathan Cebon John W. Kelly Rory Wolfe Alexander Dobrovic Catriona McLean Grant A. McArthur 《Pigment cell & melanoma research》2014,27(6):1117-1125
Activating mutations in the GTPase RAC1 are a recurrent event in cutaneous melanoma. We investigated the clinical and pathological associations of RAC1P29S in a cohort of 814 primary cutaneous melanomas with known BRAF and NRAS mutation status. The RAC1P29S mutation had a prevalence of 3.3% and was associated with increased thickness (OR=1.6 P = 0.001), increased mitotic rate (OR=1.3 P = 0.03), ulceration (OR=2.4 P = 0.04), nodular subtype (OR=3.4 P = 0.004), and nodal disease at diagnosis (OR=3.3 P = 0.006). BRAF mutant tumors were also associated with nodal metastases (OR=1.9 P = 0.004), despite being thinner at diagnosis than BRAF WT (median 1.2 mm versus 1.6 mm, P < 0.001). Immunohistochemical analysis of 51 melanomas revealed that 47% were immunoreactive for RAC1. Melanomas were more likely to show RAC1 immunoreactivity if they were BRAF mutant (OR=5.2 P = 0.01). RAC1 may therefore be important in regulating the early migration of BRAF mutant tumors. RAC1 mutations are infrequent in primary melanomas but may accelerate disease progression. 相似文献
9.
《Cell cycle (Georgetown, Tex.)》2013,12(11):1845-1852
Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3’UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma. 相似文献
10.
Adriana Sanna Katja Harbst Iva Johansson Gustav Christensen Martin Lauss Shamik Mitra Frida Rosengren Jari Hkkinen Johan Vallon‐Christersson Hkan Olsson sa Ingvar Karolin Isaksson Christian Ingvar Kari Nielsen Gran Jnsson 《Pigment cell & melanoma research》2020,33(3):480-489
Chronic sun‐damaged (CSD) melanoma represents 10%–20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra‐tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra‐deep targeted sequencing of 40 cancer‐associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in‐transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma‐related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes. 相似文献
11.
Elcie Chan Rajeshvari Patel Sunitha Nallur Elena Ratner Antonella Bacchiocchi Kathleen Hoyt Sebastian Szpakowski Sirie Godshalk Stephan Ariyan Mario Sznol Ruth Halaban Michael Krauthammer David Tuck Frank J Slack Joanne Barnes Weidhaas 《Cell cycle (Georgetown, Tex.)》2011,10(11):1845-1852
Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3′UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma.Key words: melanoma, microRNA profiling, biomarker, acral, KRAS-variant, SNP 相似文献
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R. Mark Simpson Boris C. Bastian Helen T. Michael Joshua D. Webster Manju L. Prasad Catherine M. Conway Victor M. Prieto Joy M. Gary Michael H. Goldschmidt D. Glen Esplin Rebecca C. Smedley Adriano Piris Donald J. Meuten Matti Kiupel Chyi‐Chia R. Lee Jerrold M. Ward Jennifer E. Dwyer Barbara J. Davis Miriam R. Anver Alfredo A. Molinolo Shelley B. Hoover Jaime Rodriguez‐Canales Stephen M. Hewitt 《Pigment cell & melanoma research》2014,27(1):37-47
Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun‐exposed sites. Most occur in the oral cavity, with a subset having intra‐epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ‐line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c‐kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model. 相似文献
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Clinicopathological characteristics associated with BRAFK601E and BRAFL597 mutations in melanoma 下载免费PDF全文
Mark Voskoboynik Victoria Mar Sonia Mailer Andrew Colebatch Anne Fennessy Aleksandra Logan Chelsee Hewitt Jonathon Cebon John Kelly Grant McArthur 《Pigment cell & melanoma research》2016,29(2):222-228
BRAF mutations at codons L597 and K601 occur uncommonly in melanoma. Clinical and pathological associations of these mutations were investigated in a cohort of 1119 patients with known BRAF mutation status. A BRAF mutation was identified in 435 patients; Mutations at L597 and the K601E mutation were seen in 3.4 and 3.2% of these, respectively. K601E melanomas tended to occur in male patients, a median age of 58 yr, were generally found on the trunk (64%) and uncommonly associated with chronically sun‐damaged (CSD) skin. BRAF L597 melanomas occurred in older patients (median 66 yr), but were associated with CSD skin (extremities or head and neck location – 73.3%, P = 0.001). Twenty‐three percent of patients with V600E‐ and 43% of patients with K601E‐mutant melanomas presented with nodal disease at diagnosis compared to just 14% of patients with BRAF wild‐type tumors (P = 0.001 and 0.006, respectively). Overall, these mutations represent a significant minority of BRAF mutations, but have distinct clinicopathological phenotypes and clinical behaviors. 相似文献
14.
Suzanne Shelly May B. Chien Becky Yip Michael S. Kent Alain P. Theon Jennifer L. McCallan Cheryl A. London 《Mammalian genome》2005,16(3):211-217
An activating mutation in codon 599 of BRAF has been identified in approximately 60% of human cutaneous nevi and melanomas, but not melanomas of mucosal origin. The purpose of this study was to determine if BRAF mutations occur in canine oral malignant melanomas. The canine BRAF gene was first cloned from normal canine testicular cDNA, and a novel previously unreported splice variant involving exon 5 was identified during this process. To screen canine melanoma samples for BRAF mutation in codon 599, cDNA and genomic DNA were isolated from canine malignant melanoma cell lines and primary tumor samples respectively, all from cases seen at the Veterinary Medical Teaching Hospital at the University of California, Davis. Polymerase chain reaction (PCR) was performed for exon 15 using primers based at the 5 end of exon 15 and the 5 end of intron 15 and the resultant products were directly sequenced. No mutations in codon 599 or exon 15 were identified in any of the 17 samples evaluated. However, all of the melanoma cell lines expressed BRAF and demonstrated high levels of basal ERK phosphorylation suggesting that dysregulation of this pathway is present. Therefore, similar to the case with human mucosal melanomas, canine oral malignant melanomas do not possess codon 599 BRAF mutations commonly identified in human cutaneous melanomas. This finding supports the notion that melanomas arising from non-sun-exposed sites exhibit distinct mechanisms of molecular transformation. 相似文献
15.
Nancy E. Thomas Nathaniel A. Slater Sharon N. Edmiston Xin Zhou Pei‐Fen Kuan Pamela A. Groben Craig C. Carson Honglin Hao Eloise Parrish Stergios J. Moschos Marianne Berwick David W. Ollila Kathleen Conway 《Pigment cell & melanoma research》2014,27(6):1097-1105
DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina GoldenGate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Arraywide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n = 235) divided the melanoma samples into three clusters, including a highly methylated cluster that was positively associated with Breslow thickness and an intermediately methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation‐defined subsets in melanomas with increased methylation associated with Breslow thickness. 相似文献
16.
Maleno I Aptsiauri N Cabrera T Gallego A Paschen A López-Nevot MA Garrido F 《Immunogenetics》2011,63(2):65-71
Downregulation or total loss of HLA class I expression on tumor cells is known as a mechanism of cancer immune escape. Alterations
of the HLA phenotype are frequently due to mutations affecting genes encoding the HLA class I heavy chains located on chromosome
6p21 or the β2-microglobulin (β2m) gene encoding the light chain of the HLA complex located on chromosome 15q21. Frequently
irreversible total loss of HLA class I molecules is due to the coincidence of two molecular events, the mutation of one β2m
gene and the loss of the second copy. The latter is detectable as loss of heterozygosity (LOH) of microsatellite markers in
the β2m region on chromosome 15q21 (LOH-15q21). Thus, LOH-15q21 might be an important event in the processes of HLA class
I downregulation and total loss. Here we studied the frequency of LOH-15q21 in tumor tissues of different entities. By determining
the status of heterozygosity of two microsatellite markers we detected LOH-15q21 in 44% of bladder carcinomas (n = 69), in 35% of colon carcinomas (n = 95), in 16% of melanomas (n = 70) but only in 7% of renal cancers (n = 45). Moreover, we observed a frequent coincidence of LOH-15q21 and LOH-6p21 in colorectal carcinoma, bladder carcinoma
and melanoma, but not for renal carcinoma. We believe that the high incidence of LOH-15q21 in some malignancies and especially
the coincidence of LOH-15q21 and LOH-6p21 might have a strong impact on tumor immunogenicity and on the efficiency of cancer
immunotherapy. 相似文献
17.
The mutational burden of acral melanoma revealed by whole‐genome sequencing and comparative analysis
Gordon Stamp J. Meirion Thomas Andrew Hayes Dirk Strauss Mike Gavrielides Wei Xing Martin Gore James Larkin Richard Marais 《Pigment cell & melanoma research》2014,27(5):835-838
Acral melanoma is a subtype of melanoma with distinct epidemiological, clinical and mutational profiles. To define the genomic alterations in acral melanoma, we conducted whole‐genome sequencing and SNP array analysis of five metastatic tumours and their matched normal genomes. We identified the somatic mutations, copy number alterations and structural variants in these tumours and combined our data with published studies to identify recurrently mutated genes likely to be the drivers of acral melanomagenesis. We compared and contrasted the genomic landscapes of acral, mucosal, uveal and common cutaneous melanoma to reveal the distinctive mutational characteristics of each subtype. 相似文献
18.
A. Fernández‐Rodríguez J. Estellé A. Blin M. Muñoz F. Créchet F. Demenais S. Vincent‐Naulleau E. Bourneuf 《Animal genetics》2014,45(3):445-448
KIT mutations have been detected in different cancer subtypes, including melanoma. The gene also has been extensively studied in farm animals for its prominent role in coat color. The present work aimed at detecting KIT variants in a porcine model of cutaneous melanoma, the melanoblastoma‐bearing Libechov Minipig (MeLiM). By sequencing exons and intron borders, 36 SNPs and one indel were identified. Of 10 coding SNPs, three were non‐synonymous mutations, likely to affect the protein conformation. A promising variant, located in exon 19 (p.Val870Ala), was genotyped in a MeLiM × Duroc cross, and an association analysis was conducted on several melanoma‐related traits. This variant showed a significant association with melanoma development, tumor ulceration and cutaneous invasion. In conclusion, although the KIT gene would not be a major causal gene for melanoma development in pig, its genetic variation could be influencing this trait. 相似文献
19.
Linda Gao Marjon A. Smit Joost J. van den Oord Jelle J. Goeman Els M. E. Verdegaal Sjoerd H. van der Burg Marguerite Stas Samuel Beck Nelleke A. Gruis Cornelis P. Tensen Rein Willemze Daniel S. Peeper Remco van Doorn 《Pigment cell & melanoma research》2013,26(4):542-554
The involvement of epigenetic alterations in the pathogenesis of melanoma is increasingly recognized. Here, we performed genome‐wide DNA methylation analysis of primary cutaneous melanoma and benign melanocytic nevus interrogating 14 495 genes using BeadChip technology. This genome‐wide view of promoter methylation in primary cutaneous melanoma revealed an array of recurrent DNA methylation alterations with potential diagnostic applications. Among 106 frequently hypermethylated genes, there were many novel methylation targets and tumor suppressor genes. Highly recurrent methylation of the HOXA9, MAPK13, CDH11, PLEKHG6, PPP1R3C, and CLDN11 genes was established. Promoter methylation of MAPK13, encoding p38δ, was present in 67% of primary and 85% of metastatic melanomas. Restoration of MAPK13 expression in melanoma cells exhibiting epigenetic silencing of this gene reduced proliferation, indicative of tumor suppressive functions. This study demonstrates that DNA methylation alterations are widespread in melanoma and suggests that epigenetic silencing of MAPK13 contributes to melanoma progression. 相似文献
20.
Comparison of Xiphophorus and human melanoma transcriptomes reveals conserved pathway interactions 下载免费PDF全文
Yuan Lu Mikki Boswell William Boswell Susanne Kneitz Michael Hausmann Barbara Klotz Janine Regneri Markita Savage Angel Amores John Postlethwait Wesley Warren Manfred Schartl Ronald Walter 《Pigment cell & melanoma research》2018,31(4):496-508