Genetics and Genomics of Melanoma

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 33036

Special Issue Editor

Melanoma Institute Australia, The University of Sydney, Sydney, Australia
Interests: cancer; immunotherapy; gene expression profiling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Melanoma is a malignant cancer that originates from the pigment cells (melanocytes) of the skin, accounting for the majority of skin-cancer-related deaths. The field of melanoma genetics and genomics has been advancing at a rapid pace, offering a wealth of possibilities for translational applications. Cutting-edge genomic techniques allow researchers to elucidate copy number variations, chromosome structural alterations, gene expression aberration, epigenetic changes and immunogenomics that underpin melanoma genesis, progression and response to therapy.

In this Special Issue, manuscripts focusing on state-of-the-art approaches in basic, translational and clinical research on melanoma will be featured. These approaches include but are not limited to novel single-cell or single-nuclei sequencing, new bioinformatics and statistical methods, mass cytometry, multiplexed immunofluorescence, tumour xenografts and organoid. This Special Issue showcases the recent discovery of melanoma development and potential biomarkers or therapeutic targets at the genetic and genomic level.

Dr. Camelia Quek
Guest Editor

Manuscript Submission Information

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Keywords

  • melanoma
  • gene expression
  • genomics
  • genetics
  • transcriptomics
  • single-cell
  • computational
  • bioinformatics
  • sequencing
  • functional genomics
  • cancer therapy

Published Papers (12 papers)

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Editorial

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3 pages, 156 KiB  
Editorial
Genetics and Genomics of Melanoma: Current Progress and Future Directions
by Camelia Quek
Genes 2023, 14(1), 232; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14010232 - 16 Jan 2023
Cited by 1 | Viewed by 1497
Abstract
Melanoma is a form of skin cancer that develops in the skin’s pigment cells, known as melanocytes, and can spread via blood and the lymphatic system to nearby tissues or distant organs in the body [...] Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)

Research

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13 pages, 4828 KiB  
Article
Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma
by Mak B. Djulbegovic, David J. Taylor, Vladimir N. Uversky, Anat Galor, Carol L. Shields and Carol L. Karp
Genes 2022, 13(10), 1703; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101703 - 22 Sep 2022
Cited by 6 | Viewed by 1786
Abstract
Background: Specific subvariants of uveal melanoma (UM) are associated with increased rates of metastasis compared to other subvariants. BRCA1 (BReast CAncer gene 1)-associated protein-1 (BAP1) is encoded by a gene that has been linked to aggressive behavior in UM. Methods: We evaluated BAP1 [...] Read more.
Background: Specific subvariants of uveal melanoma (UM) are associated with increased rates of metastasis compared to other subvariants. BRCA1 (BReast CAncer gene 1)-associated protein-1 (BAP1) is encoded by a gene that has been linked to aggressive behavior in UM. Methods: We evaluated BAP1 for the presence of intrinsically disordered protein regions (IDPRs) and its protein–protein interactions (PPI). We evaluated specific sequence-based features of the BAP1 protein using a set of bioinformatic databases, predictors, and algorithms. Results: We show that BAP1’s structure contains extensive IDPRs as it is highly enriched in proline residues (the most disordered amino acid; p-value < 0.05), the average percent of predicted disordered residues (PPDR) was 57.34%, and contains 9 disorder-based binding sites (ie. molecular recognition features (MoRFs)). BAP1’s intrinsic disorder allows it to engage in a complex PPI network with at least 49 partners (p-value < 1.0 × 10−16). Conclusion: These findings show that BAP1 contains IDPRs and an intricate PPI network. Mutations in UM that are associated with the BAP1 gene may alter the function of the IDPRs embedded into its structure. These findings develop the understanding of UM and may provide a target for potential novel therapies to treat this aggressive neoplasm. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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11 pages, 3540 KiB  
Article
Gene Expression and Mutational Profile in BAP-1 Inactivated Melanocytic Lesions of Progressive Malignancy from a Patient with Multiple Lesions
by Yan Zhou, Andrew C. Nelson, Yuyu He, Sarah A. Munro, Kyu Young Song, Evidio Domingo-Musibay and Alessio Giubellino
Genes 2022, 13(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010010 - 22 Dec 2021
Cited by 4 | Viewed by 2368
Abstract
BAP-1 (BRCA1-associated protein 1) inactivated melanocytic lesions are a group of familial or sporadic lesions with unique histology and molecular features. They are of great clinical interest, at least in part due to the potential for malignant transformation and association with a familial [...] Read more.
BAP-1 (BRCA1-associated protein 1) inactivated melanocytic lesions are a group of familial or sporadic lesions with unique histology and molecular features. They are of great clinical interest, at least in part due to the potential for malignant transformation and association with a familial cancer predisposition syndrome. Here, we describe a patient with multiple spatially and temporally distinct melanocytic lesions with loss of BAP1 expression by immunohistochemistry. RNA sequencing was performed on three independent lesions spanning the morphologic spectrum: a benign nevus, an atypical tumor, and a melanoma arising from a pre-existing BAP1-inactivated nevus. The three lesions demonstrated largely distinct gene expression and mutational profiles. Gene expression analysis revealed that genes involved in receptor protein kinase pathways were progressively upregulated from nevus to melanoma. Moreover, a clear enrichment of genes regulated in response to UV radiation was found in the melanoma from this patient, as well as upregulation of MAPK pathway-related genes and several transcription factors related to melanomagenesis. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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11 pages, 6456 KiB  
Article
MiR-138-5p Suppresses Cell Growth and Migration in Melanoma by Targeting Telomerase Reverse Transcriptase
by Estefanía Tarazón, Blanca de Unamuno Bustos, Rosa Murria Estal, Gema Pérez Simó, Antonio Sahuquillo Torralba, Javier Simarro, Sarai Palanca Suela and Rafael Botella Estrada
Genes 2021, 12(12), 1931; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121931 - 30 Nov 2021
Cited by 10 | Viewed by 1880
Abstract
Recent evidence suggests the existence of a miRNA regulatory network involving human telomerase reverse transcriptase gene (hTERT), with miR-138-5p playing a central role in many types of cancers. However, little is known about the regulation of hTERT expression by microRNA (miRNAs) [...] Read more.
Recent evidence suggests the existence of a miRNA regulatory network involving human telomerase reverse transcriptase gene (hTERT), with miR-138-5p playing a central role in many types of cancers. However, little is known about the regulation of hTERT expression by microRNA (miRNAs) in melanocytic tumors. Here, we investigated the effects of miR-138-5p in hTERT regulation in melanoma cells lines. In vitro studies demonstrated higher miR-138-5p and lower hTERT messenger RNA (mRNA) expression in human epidermal melanocytes, compared with melanoma cell lines (A2058, A375, SK-MEL-28) by quantitative polymerase chain reaction (qPCR) observing a negative correlation between them. A2058 melanoma cells were selected to be transfected with miR-138-5p mimic or inhibitor. Using luciferase assay, hTERT was identified as a direct target of this miRNA. Overexpression of miR-138-5p detected by Western blot revealed a decrease in hTERT protein expression (p = 0.012), and qPCR showed a reduction in telomerase activity (p < 0.001). Moreover, suppressions in cell growth (p = 0.035) and migration abilities (p = 0.015) were observed in A2058-transfected cells using thiazolyl blue tetrazolium bromide and flow cytometry, respectively. This study identifies miR-138-5p as a crucial tumor suppressor miRNA involved in telomerase regulation. Targeting it as a combination therapy with immunotherapy or targeted therapies could be used in advanced melanoma treatment; however, more preclinical studies are necessary. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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14 pages, 4684 KiB  
Article
Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma
by Mak B. Djulbegovic, Vladimir N. Uversky, J. William Harbour, Anat Galor and Carol L. Karp
Genes 2021, 12(10), 1625; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101625 - 15 Oct 2021
Cited by 5 | Viewed by 1835
Abstract
In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for [...] Read more.
In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR®) and the Search Tool for the Retrieval of Interacting Genes (STRING®). Our PONDR® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected (p-value < 1.0 × 10−16). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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12 pages, 436 KiB  
Communication
Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients
by Elisabetta Vergani, Simona Frigerio, Matteo Dugo, Andrea Devecchi, Erika Feltrin, Loris De Cecco, Viviana Vallacchi, Mara Cossa, Lorenza Di Guardo, Siranoush Manoukian, Bernard Peissel, Andrea Ferrari, Gianfrancesco Gallino, Andrea Maurichi, Licia Rivoltini, Marialuisa Sensi and Monica Rodolfo
Genes 2021, 12(9), 1440; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091440 - 18 Sep 2021
Cited by 2 | Viewed by 2760
Abstract
The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, [...] Read more.
The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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12 pages, 1033 KiB  
Article
NGS Analysis of Liquid Biopsy (LB) and Formalin-Fixed Paraffin-Embedded (FFPE) Melanoma Samples Using Oncomine™ Pan-Cancer Cell-Free Assay
by Magdalena Olbryt, Marcin Rajczykowski, Wiesław Bal, Anna Fiszer-Kierzkowska, Alexander Jorge Cortez, Magdalena Mazur, Rafał Suwiński and Wiesława Widłak
Genes 2021, 12(7), 1080; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071080 - 16 Jul 2021
Cited by 4 | Viewed by 3350
Abstract
Next-generation sequencing (NGS) in liquid biopsies may contribute to the diagnosis, monitoring, and personalized therapy of cancer through the real-time detection of a tumor’s genetic profile. There are a few NGS platforms offering high-sensitivity sequencing of cell-free DNA (cfDNA) samples. The aim of [...] Read more.
Next-generation sequencing (NGS) in liquid biopsies may contribute to the diagnosis, monitoring, and personalized therapy of cancer through the real-time detection of a tumor’s genetic profile. There are a few NGS platforms offering high-sensitivity sequencing of cell-free DNA (cfDNA) samples. The aim of this study was to evaluate the Ion AmpliSeq HD Technology for targeted sequencing of tumor and liquid biopsy samples from patients with fourth-stage melanoma. Sequencing of 30 samples (FFPE tumor and liquid biopsy) derived from 14 patients using the Oncomine™ Pan-Cancer Cell-Free Assay was performed. The analysis revealed high concordance between the qPCR and NGS results of the BRAF mutation in FFPE samples (91%), as well as between the FFPE and liquid biopsy samples (91%). The plasma-tumor concordance of the non-BRAF mutations was 28%. A total of 17 pathogenic variants in 14 genes (from 52-gene panel), including TP53, CTNNB1, CCND1, MET, MAP2K1, and GNAS, were identified, with the CTNNB1S45F variant being the most frequent. A positive correlation between the LDH level and cfDNA concentration as well as negative correlation between the LDH level and time to progression was confirmed in a 22-patient cohort. The analysis showed both the potential and limitations of liquid biopsy genetic profiling using HD technology and the Ion Torrent platform. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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19 pages, 3140 KiB  
Article
VECTOR: An Integrated Correlation Network Database for the Identification of CeRNA Axes in Uveal Melanoma
by Cristina Barbagallo, Antonio Di Maria, Adriana Alecci, Davide Barbagallo, Salvatore Alaimo, Lorenzo Colarossi, Alfredo Ferro, Cinzia Di Pietro, Michele Purrello, Alfredo Pulvirenti and Marco Ragusa
Genes 2021, 12(7), 1004; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12071004 - 29 Jun 2021
Cited by 10 | Viewed by 2139
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and, although its genetic background has been extensively studied, little is known about the contribution of non-coding RNAs (ncRNAs) to its pathogenesis. Indeed, its competitive endogenous RNA (ceRNA) regulatory network [...] Read more.
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and, although its genetic background has been extensively studied, little is known about the contribution of non-coding RNAs (ncRNAs) to its pathogenesis. Indeed, its competitive endogenous RNA (ceRNA) regulatory network comprising microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and mRNAs has been insufficiently explored. Thanks to UM findings from The Cancer Genome Atlas (TCGA), it is now possible to statistically elaborate these data to identify the expression relationships among RNAs and correlative interaction data. In the present work, we propose the VECTOR (uVeal mElanoma Correlation NeTwORk) database, an interactive tool that identifies and visualizes the relationships among RNA molecules, based on the ceRNA model. The VECTOR database contains: (i) the TCGA-derived expression correlation values of miRNA-mRNA, miRNA-lncRNA and lncRNA-mRNA pairs combined with predicted or validated RNA-RNA interactions; (ii) data of sense-antisense sequence overlapping; (iii) correlation values of Transcription Factor (TF)-miRNA, TF-lncRNA, and TF-mRNA pairs associated with ChiPseq data; (iv) expression data of miRNAs, lncRNAs and mRNAs both in UM and physiological tissues. The VECTOR web interface can be queried, by inputting the gene name, to retrieve all the information about RNA signaling and visualize this as a graph. Finally, VECTOR provides a very detailed picture of ceRNA networks in UM and could be a very useful tool for researchers studying RNA signaling in UM. The web version of Vector is freely available at the URL reported at the end of the Introduction. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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Review

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16 pages, 314 KiB  
Review
Unravelling Tumour Microenvironment in Melanoma at Single-Cell Level and Challenges to Checkpoint Immunotherapy
by Xinyu Bai and Camelia Quek
Genes 2022, 13(10), 1757; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101757 - 28 Sep 2022
Cited by 4 | Viewed by 1983
Abstract
Melanoma is known as one of the most immunogenic tumours and is often characterised by high mutation burden, neoantigen load and immune infiltrate. The application of immunotherapies has led to impressive improvements in the clinical outcomes of advanced stage melanoma patients. The standard [...] Read more.
Melanoma is known as one of the most immunogenic tumours and is often characterised by high mutation burden, neoantigen load and immune infiltrate. The application of immunotherapies has led to impressive improvements in the clinical outcomes of advanced stage melanoma patients. The standard of care immunotherapies leverage the host immunological influence on tumour cells, which entail complex interactions among the tumour, stroma, and immune cells at the tumour microenvironmental level. However, not all cancer patients can achieve a long-term durable response to immunotherapy, and a significant proportion of patients develops resistance and still die from their disease. Owing to the multi-faceted problems of tumour and microenvironmental heterogeneity, identifying the key factors underlying tumour progression and immunotherapy resistance poses a great challenge. In this review, we outline the main challenges to current cancer immunotherapy research posed by tumour heterogeneity and microenvironment complexities including genomic and transcriptomic variability, selective outgrowth of tumour subpopulations, spatial and temporal tumour heterogeneity and the dynamic state of host immunity and microenvironment orchestration. We also highlight the opportunities to dissect tumour heterogeneity using single-cell sequencing and spatial platforms. Integrative analyses of large-scale datasets will enable in-depth exploration of biological questions, which facilitates the clinical application of translational research. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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9 pages, 463 KiB  
Review
Bioinformatic and Machine Learning Applications in Melanoma Risk Assessment and Prognosis: A Literature Review
by Emily Z. Ma, Karl M. Hoegler and Albert E. Zhou
Genes 2021, 12(11), 1751; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111751 - 30 Oct 2021
Cited by 7 | Viewed by 2490
Abstract
Over 100,000 people are diagnosed with cutaneous melanoma each year in the United States. Despite recent advancements in metastatic melanoma treatment, such as immunotherapy, there are still over 7000 melanoma-related deaths each year. Melanoma is a highly heterogenous disease, and many underlying genetic [...] Read more.
Over 100,000 people are diagnosed with cutaneous melanoma each year in the United States. Despite recent advancements in metastatic melanoma treatment, such as immunotherapy, there are still over 7000 melanoma-related deaths each year. Melanoma is a highly heterogenous disease, and many underlying genetic drivers have been identified since the introduction of next-generation sequencing. Despite clinical staging guidelines, the prognosis of metastatic melanoma is variable and difficult to predict. Bioinformatic and machine learning analyses relying on genetic, clinical, and histopathologic inputs have been increasingly used to risk stratify melanoma patients with high accuracy. This literature review summarizes the key genetic drivers of melanoma and recent applications of bioinformatic and machine learning models in the risk stratification of melanoma patients. A robustly validated risk stratification tool can potentially guide the physician management of melanoma patients and ultimately improve patient outcomes. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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21 pages, 877 KiB  
Review
High-Dimensional Single-Cell Transcriptomics in Melanoma and Cancer Immunotherapy
by Camelia Quek, Xinyu Bai, Georgina V. Long, Richard A. Scolyer and James S. Wilmott
Genes 2021, 12(10), 1629; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101629 - 16 Oct 2021
Cited by 8 | Viewed by 4923
Abstract
Recent advances in single-cell transcriptomics have greatly improved knowledge of complex transcriptional programs, rapidly expanding our knowledge of cellular phenotypes and functions within the tumour microenvironment and immune system. Several new single-cell technologies have been developed over recent years that have enabled expanded [...] Read more.
Recent advances in single-cell transcriptomics have greatly improved knowledge of complex transcriptional programs, rapidly expanding our knowledge of cellular phenotypes and functions within the tumour microenvironment and immune system. Several new single-cell technologies have been developed over recent years that have enabled expanded understanding of the mechanistic cells and biological pathways targeted by immunotherapies such as immune checkpoint inhibitors, which are now routinely used in patient management with high-risk early-stage or advanced melanoma. These technologies have method-specific strengths, weaknesses and capabilities which need to be considered when utilising them to answer translational research questions. Here, we provide guidance for the implementation of single-cell transcriptomic analysis platforms by reviewing the currently available experimental and analysis workflows. We then highlight the use of these technologies to dissect the tumour microenvironment in the context of cancer patients treated with immunotherapy. The strategic use of single-cell analytics in clinical settings are discussed and potential future opportunities are explored with a focus on their use to rationalise the design of novel immunotherapeutic drug therapies that will ultimately lead to improved cancer patient outcomes. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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21 pages, 2313 KiB  
Review
Genetic and Genomic Pathways of Melanoma Development, Invasion and Metastasis
by Jyoti Motwani and Michael R. Eccles
Genes 2021, 12(10), 1543; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101543 - 28 Sep 2021
Cited by 12 | Viewed by 4141
Abstract
Melanoma is a serious form of skin cancer that accounts for 80% of skin cancer deaths. Recent studies have suggested that melanoma invasiveness is attributed to phenotype switching, which is a reversible type of cell behaviour with similarities to epithelial to mesenchymal transition. [...] Read more.
Melanoma is a serious form of skin cancer that accounts for 80% of skin cancer deaths. Recent studies have suggested that melanoma invasiveness is attributed to phenotype switching, which is a reversible type of cell behaviour with similarities to epithelial to mesenchymal transition. Phenotype switching in melanoma is reported to be independent of genetic alterations, whereas changes in gene transcription, and epigenetic alterations have been associated with invasiveness in melanoma cell lines. Here, we review mutational, transcriptional, and epigenomic alterations that contribute to tumour heterogeneity in melanoma, and their potential to drive melanoma invasion and metastasis. We also discuss three models that are hypothesized to contribute towards aspects of tumour heterogeneity and tumour progression in melanoma, namely the clonal evolution model, the cancer stem cell model, and the phenotype switching model. We discuss the merits and disadvantages of each model in explaining tumour heterogeneity in melanoma, as a precursor to invasion and metastasis. Full article
(This article belongs to the Special Issue Genetics and Genomics of Melanoma)
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