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Cancers
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Epigenetic Dysregulation in Melanoma
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Epigenetic Dysregulation in Melanoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 7666

Special Issue Editor

Dr. Jessamy Tiffen

E-Mail Website
Guest Editor
Melanoma Epigenetics Laboratory, Centenary Institute, University of Sydney, Camperdown, NSW 2050, Australia
Interests: melanoma; epigenetics; histone modifiers; therapy resistance; mouse models

Special Issue Information

Dear Colleagues,

Despite recent advancements in targeted therapy and immunotherapy, patients are still dying from melanoma. These treatments do not work for everyone and their success is hindered by the development of resistance to therapy that occurs in the majority of responding patients. New therapeutic targets are urgently needed. Epigenetic dysregulation is a frequent event in melanoma. Such changes are increasingly recognised to govern major hallmarks of cancer that drive melanoma progression and therapy resistance mechanisms. While much of the focus traditionally has been on DNA methylation, the field has exploded in recent years to include a complex network of players that shape chromatin architecture.   

Epigenetic regulators have a profound influence on global gene expression. They allow cancer cells to silence genes deleterious to cancer cell growth while activating the transcription of genes advantageous to them, without altering the DNA sequence. Essential in normal development, epigenetic modifications allow for the differentiation of vastly different cell types from embryonic stem cells, despite containing an identical genome. These epigenetic processes are, however, frequently hijacked in cancer cells including melanoma. In the largest melanoma whole-genome sequencing study ever performed worldwide, driver mutations were identified in several key epigenetic pathways, including histone modifiers (48%), chromatin remodellers (38%), and DNA methylation (19%).

In the context of melanoma drug resistance, it has been demonstrated that rare populations of dedifferentiated, slow-cycling cells persist after drug treatment and contribute to eventual relapse. Studies have shown that the emergence of these drug-tolerant cells are associated with changes in the expression of epigenetic modifiers such as DNA methyltransferases, histone demethylases/methyltransferases, and deacetylases, all of which are druggable targets that warrant further investigation.

Recently developed drugs that inhibit epigenetic regulators are proving to be safe and effective against a range of cancers in early clinical studies, but their potential to treat melanoma has not been assessed. This Special Issue will highlight the role of epigenetic dysregulation in melanoma progression and treatment resistance, with an emphasis on opportunities for therapeutic interventions in this notoriously aggressive and biologically plastic disease.

Dr. Jessamy Tiffen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • melanoma
  • epigenetics
  • histone modifiers
  • chromatin remodellers
  • DNA methyltransferases/demethylases
  • non-coding RNAs
  • treatment resistance
  • targeted therapy

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Published Papers (3 papers)

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Research

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18 pages, 1525 KiB  
Article
Genetic and Methylation Analysis of CTNNB1 in Benign and Malignant Melanocytic Lesions
by Anne Zaremba, Philipp Jansen, Rajmohan Murali, Anand Mayakonda, Anna Riedel, Dieter Krahl, Hans Burkhardt, Stefan John, Cyrill Géraud, Manuel Philip, Julia Kretz, Inga Möller, Nadine Stadtler, Antje Sucker, Annette Paschen, Selma Ugurel, Lisa Zimmer, Elisabeth Livingstone, Susanne Horn, Christoph Plass, Dirk Schadendorf, Eva Hadaschik, Pavlo Lutsik and Klaus Griewankadd Show full author list remove Hide full author list
Cancers 2022, 14(17), 4066; https://doi.org/10.3390/cancers14174066 - 23 Aug 2022
Cited by 1 | Viewed by 2162
Abstract
Melanocytic neoplasms have been genetically characterized in detail during the last decade. Recurrent CTNNB1 exon 3 mutations have been recognized in the distinct group of melanocytic tumors showing deep penetrating nevus-like morphology. In addition, they have been identified in 1–2% of advanced melanoma. [...] Read more.
Melanocytic neoplasms have been genetically characterized in detail during the last decade. Recurrent CTNNB1 exon 3 mutations have been recognized in the distinct group of melanocytic tumors showing deep penetrating nevus-like morphology. In addition, they have been identified in 1–2% of advanced melanoma. Performing a detailed genetic analysis of difficult-to-classify nevi and melanomas with CTNNB1 mutations, we found that benign tumors (nevi) show characteristic morphological, genetic and epigenetic traits, which distinguish them from other nevi and melanoma. Malignant CTNNB1-mutant tumors (melanomas) demonstrated a different genetic profile, instead grouping clearly with other non-CTNNB1 melanomas in methylation assays. To further evaluate the role of CTNNB1 mutations in melanoma, we assessed a large cohort of clinically sequenced melanomas, identifying 38 tumors with CTNNB1 exon 3 mutations, including recurrent S45 (n = 13, 34%), G34 (n = 5, 13%), and S27 (n = 5, 13%) mutations. Locations and histological subtype of CTNNB1-mutated melanoma varied; none were reported as showing deep penetrating nevus-like morphology. The most frequent concurrent activating mutations were BRAF V600 (n = 21, 55%) and NRAS Q61 (n = 13, 34%). In our cohort, four of seven (58%) and one of nine (11%) patients treated with targeted therapy (BRAF and MEK Inhibitors) or immune-checkpoint therapy, respectively, showed disease control (partial response or stable disease). In summary, CTNNB1 mutations are associated with a unique melanocytic tumor type in benign tumors (nevi), which can be applied in a diagnostic setting. In advanced disease, no clear characteristics distinguishing CTNNB1-mutant from other melanomas were observed; however, studies of larger, optimally prospective, cohorts are warranted. Full article
(This article belongs to the Special Issue Epigenetic Dysregulation in Melanoma)
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16 pages, 2948 KiB  
Article
The Prognostic Value of miR-125b, miR-200c and miR-205 in Primary Cutaneous Malignant Melanoma Is Independent of BRAF Mutational Status
by Beatriz Sánchez-Sendra, José F. González-Muñoz, Silvia Pérez-Debén and Carlos Monteagudo
Cancers 2022, 14(6), 1532; https://doi.org/10.3390/cancers14061532 - 16 Mar 2022
Cited by 2 | Viewed by 2069
Abstract
BRAF mutations are present in around 50% of cutaneous malignant melanomas and are related to a poor outcome in advanced-stage melanoma patients. miRNAs are epigenetic regulators that modulate different cellular processes in cancer, including melanoma development and progression. However, there are no studies [...] Read more.
BRAF mutations are present in around 50% of cutaneous malignant melanomas and are related to a poor outcome in advanced-stage melanoma patients. miRNAs are epigenetic regulators that modulate different cellular processes in cancer, including melanoma development and progression. However, there are no studies on the potential associations of the genetic alterations of the BRAF gene with miRNA expression in primary cutaneous melanomas. Here, in order to analyze the influence of BRAF mutations in the ability of selected miRNAs to predict clinical outcome and patient survival at the time of diagnosis, we studied the prognostic value of miR-125b, miR-200c and miR-205 expression depending on the BRAF mutational status in fresh, frozen primary tumor specimens. For this purpose, RNA was extracted for studying both BRAF mutations by Sanger sequencing and miRNA expression. Our results indicate that, although there seems to be a slight preference for their predictive ability in the BRAF mutated group, the expression of these three miRNAs serves effectively to predict the clinical outcome of melanoma patients independently of BRAF mutational status at the time of primary tumor diagnosis. Full article
(This article belongs to the Special Issue Epigenetic Dysregulation in Melanoma)
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Review

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22 pages, 1879 KiB  
Review
Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies
by Andrey Rubanov, Pietro Berico and Eva Hernando
Cancers 2022, 14(23), 5858; https://doi.org/10.3390/cancers14235858 - 28 Nov 2022
Cited by 6 | Viewed by 2799
Abstract
Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty [...] Read more.
Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAFV600E and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies. Full article
(This article belongs to the Special Issue Epigenetic Dysregulation in Melanoma)
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