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Molecular Biology, Immune Surveillance and Progressive Disease: New Insights in Melanoma Research

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 13571

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Special Issue Editor

Dr. Daniela Mihic-Probst

E-Mail Website
Guest Editor

Faculty of Medicine, University of Zurich, 8091 Zurich, Switzerland
Interests: melanoma; cancer cells; genetics; tumor progress; tumor cell plasticity; immune therapy related adverse events; melanoma sentinel biopsy; skin

Special Issue Information

Dear Colleagues,

Molecular analysis has revolutionized both the diagnostic and therapeutic approach to cancer. Histology of melanoma metastases can mimic many different tumor types, especially if non-pigmented. While some patients with metastatic disease have no melanoma history given complete primary melanoma regression or incorrect initial nevus diagnosis, immunohistochemistry with metastatic positivity for melanocytic markers/S-100 protein enables correct diagnosis. However, some transdifferentiated melanomas are negative for those markers and may even show aberrant mesenchymal and/or epidermal differentiation. In early 2000, polymerase chain reaction and, later on, next-generation sequencing (NGS) detected BRAF, NRAS, and other driver mutations in melanoma. Identifying such melanoma driver mutations enables correct diagnosis in transdifferentiated melanomas. Furthermore, NGS is increasingly used for the assessment of diagnostically difficult melanocytic lesions with morphologically uncertain malignant potential.

New medications targeting driver genes as well as immune check-point inhibitory medications have revolutionized melanoma therapy. Molecular analysis is critical here too to evaluate whether medication is available for the present driver mutation. Furthermore, tumors with high mutational burden and many tumor-associated macrophages are better responders to immune checkpoint inhibitory therapies.

Molecular analysis has demonstrated that melanomas are inconsistent among each other. Cutaneous, acral, uveal, and mucosal melanomas have site-specific mutations and different mutational burden. However, epigenetic influences should not be underestimated, as methylom analyses have shown in brain tumors.

The aim of this Special Issue is to provide studies and reviews offering insights into molecular biology, immune surveillance, and tumor progression of melanoma.

Dr. Daniela Mihic-Probst
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 short 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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
Metastasis
Angiotropism
Tumor cell plasticitiy
Stem cells
Hypoxia
Angiogenesis
Melanoma-associated macrophages
Regression
Immune surveillance
immune check point inhibitor
tumor targeting therapy
melanoma therapy
melanoma therapy adverse events

Published Papers (6 papers)

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Research

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14 pages, 3050 KiB

Open AccessArticle

Hypoxia and Ezrin Expression in Primary Melanoma Have High Prognostic Relevance

by Umberto Maccio, Alanna Mihic, Daniela Lenggenhager, Isabel Kolm, Christiane Mittmann, Mathias Heikenwälder, Anna Lorentzen and Daniela Mihic-Probst

Int. J. Mol. Sci. 2022, 23(18), 10745; https://doi.org/10.3390/ijms231810745 - 15 Sep 2022

Cited by 1 | Viewed by 1455

Abstract

Hypoxia affects tumor aggressiveness and activates pathways associated with epithelial mesenchymal transition (EMT) which are crucial for tumor progress. In this study, the correlation of hypoxia and EMT with sentinel lymph node status and tumor-specific survival was investigated in primary melanomas. CD34 for capillary count and Hypoxia inducible factor-1α (HIF-1α) as hypoxia indicators as well as Ezrin and L1-Cell Adhesion Molecule (L1CAM), both critical proteins contributing to EMT, were analyzed using immunohistochemistry in 49 melanoma patients with long follow-up (F/U, mean 110 months; range 12–263 months). We found a significant correlation between Breslow tumor thickness and Ezrin expression (p = 0.018). L1CAM expression in primary melanoma was significantly associated with HIF-1α expression (p < 0.0001) and sentinel lymph node metastasis (p = 0.011). Furthermore, low capillary count, reflecting hypoxic condition, was significantly associated with Ezrin expression (p = 0.047) and decreased tumor-specific survival (p = 0.035). In addition, patients with high Ezrin expression in their primary melanoma had a dramatic loss of life early in their F/U period (mean survival time 29 months; range 15–44 month). Our results highlight the relevance of Ezrin, L1CAM and HIF-1α as prognostic markers in melanoma patients. Additionally, we demonstrate that hypoxia in primary melanoma affects EMT and is at least partly responsible for early metastatic dissemination. Full article

(This article belongs to the Special Issue Molecular Biology, Immune Surveillance and Progressive Disease: New Insights in Melanoma Research)

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14 pages, 3418 KiB

Open AccessArticle

NTRK Gene Fusion Detection in Atypical Spitz Tumors

by Rocco Cappellesso, Filippo Nozzoli, Federica Zito Marino, Sara Simi, Francesca Castiglione, Vincenzo De Giorgi, Carlo Cota, Rebecca Senetta, Giosuè Scognamiglio, Anna Maria Anniciello, Anna Maria Cesinaro, Mario Mandalà, Andrea Gianatti, Maria Gabriella Valente, Barbara Valeri, Angela Rita Sementa, Costantino Ricci, Barbara Corti, Giandomenico Roviello, Angelo Paolo Dei Tos, Renato Franco and Daniela Massi Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(22), 12332; https://doi.org/10.3390/ijms222212332 - 15 Nov 2021

Cited by 12 | Viewed by 2618

Abstract

Atypical Spitz tumors (AST) deviate from stereotypical Spitz nevi for one or more atypical features and are now regarded as an intermediate category of melanocytic tumors with uncertain malignant potential. Activating NTRK1/NTRK3 fusions elicit oncogenic events in Spitz lesions and are targetable with kinase inhibitors. However, their prevalence among ASTs and the optimal approach for their detection is yet to be determined. A series of 180 ASTs were screened with pan-TRK immunohistochemistry and the presence of NTRK fusions was confirmed using FISH, two different RNA-based NGS panels for solid tumors, and a specific real time RT-PCR panel. Overall, 26 ASTs showed pan-TRK immunostaining. NTRK1 fusions were detected in 15 of these cases showing cytoplasmic immunoreaction, whereas NTRK3 was detected in one case showing nuclear immunoreaction. Molecular tests resulted all positive in only two ASTs (included the NTRK3 translocated), RNA-based NGS and real time RT-PCR were both positive in three cases, and FISH and real time RT-PCR in another two cases. In seven ASTs NTRK1 fusions were detected only by FISH and in two cases only by real time RT-PCR. The frequency of NTRK fusions in ASTs is 9%, with a clear prevalence of NTRK1 compared to NTRK3 alterations. Pan-TRK immunohistochemistry is an excellent screening test. Confirmation of NTRK fusions may require the use of different molecular techniques. Full article

(This article belongs to the Special Issue Molecular Biology, Immune Surveillance and Progressive Disease: New Insights in Melanoma Research)

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10 pages, 438 KiB

Open AccessCommunication

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas

by Canan Güvenç, Asier Antoranz, Anna Szumera-Ciećkiewicz, Pawel P. Teterycz, Piotr R. Rutkowski, Robert V. Rawson, Richard A. Scolyer, John F. Thompson, Julia Newton-Bishop, Marguerite Stas, Veerle Boecxstaens, Oliver Bechter, Jurgen Vercauteren, Marjan Garmyn, Joost van den Oord and Francesca Maria Bosisio

Int. J. Mol. Sci. 2021, 22(19), 10568; https://doi.org/10.3390/ijms221910568 - 29 Sep 2021

Cited by 1 | Viewed by 2084

Abstract

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5–10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues. Full article

(This article belongs to the Special Issue Molecular Biology, Immune Surveillance and Progressive Disease: New Insights in Melanoma Research)

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12 pages, 1273 KiB

Open AccessArticle

Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis

by Natasha M. van Poppelen, Jolique A. van Ipenburg, Quincy van den Bosch, Jolanda Vaarwater, Tom Brands, Bert Eussen, Frank Magielsen, Hendrikus J. Dubbink, Dion Paridaens, Erwin Brosens, Nicole Naus, Annelies de Klein, Emine Kiliç and Robert M. Verdijk

Int. J. Mol. Sci. 2021, 22(11), 5784; https://doi.org/10.3390/ijms22115784 - 28 May 2021

Cited by 17 | Viewed by 2370

Abstract

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM. Full article

(This article belongs to the Special Issue Molecular Biology, Immune Surveillance and Progressive Disease: New Insights in Melanoma Research)

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14 pages, 1326 KiB

Open AccessArticle

The Molecular Landscape of Primary Acral Melanoma: A Multicenter Study of the Italian Melanoma Intergroup (IMI)

by Lisa Elefanti, Carolina Zamuner, Paolo Del Fiore, Camilla Stagni, Stefania Pellegrini, Luigi Dall’Olmo, Alessio Fabozzi, Rebecca Senetta, Simone Ribero, Roberto Salmaso, Simone Mocellin, Franco Bassetto, Francesco Cavallin, Anna Lisa Tosi, Francesca Galuppini, Angelo Paolo Dei Tos, Chiara Menin and Rocco Cappellesso

Int. J. Mol. Sci. 2021, 22(8), 3826; https://doi.org/10.3390/ijms22083826 - 07 Apr 2021

Cited by 12 | Viewed by 2509

Abstract

Acral melanoma (AM) is a rare and aggressive subtype of melanoma affecting the palms, soles, and nail apparatus with similar incidence among different ethnicities. AM is unrelated to ultraviolet radiation and has a low mutation burden but frequent chromosomal rearrangements and gene amplifications. Next generation sequencing of 33 genes and somatic copy number variation (CNV) analysis with genome-wide single nucleotide polymorphism arrays were performed in order to molecularly characterize 48 primary AMs of Italian patients in association with clinicopathological and prognostic features. BRAF was the most commonly mutated gene, followed by NRAS and TP53, whereas TERT promoter, KIT, and ARID1A were less frequently mutated. Gains and losses were recurrently found in the 1q, 6p, 7, 8q, 20 and 22 chromosomes involving PREX2, RAC1, KMT2C, BRAF, CCND1, TERT, and AKT3 genes, and in the 6q, 9, 10, 11q and 16q chromosomes including CDKN2A, PTEN, and ADAMTS18 genes, respectively. This study confirmed the variety of gene mutations and the high load of CNV in primary AM. Some genomic alterations were associated with histologic prognostic features. BRAF mutations, found with a higher rate than previously reported, correlated with a low Breslow thickness, low mitotic count, low CNV of the AMs, and with early-stage of disease. Full article

(This article belongs to the Special Issue Molecular Biology, Immune Surveillance and Progressive Disease: New Insights in Melanoma Research)

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Review

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15 pages, 1459 KiB

Open AccessReview

Bona Fide Tumor Suppressor Genes Hypermethylated in Melanoma: A Narrative Review

by Canan Güvenç, Fien Neckebroeck, Asier Antoranz, Marjan Garmyn, Joost van den Oord and Francesca Maria Bosisio

Int. J. Mol. Sci. 2021, 22(19), 10674; https://doi.org/10.3390/ijms221910674 - 01 Oct 2021

Cited by 2 | Viewed by 1777

Abstract

Loss-of-function events in tumor suppressor genes (TSGs) contribute to the development and progression of cutaneous malignant melanoma (CMM). Epigenetic alterations are the major mechanisms of TSG inactivation, in particular, silencing by promoter CpG-island hypermethylation. TSGs are valuable tools in diagnosis and prognosis and, possibly, in future targeted therapy. The aim of this narrative review is to outline bona fide TSGs affected by promoter CpG-island hypermethylation and their functional role in the progression of CMM. We conducted a systematic literature review to identify studies providing evidence of bona fide TSGs by cell line or animal experiments. We performed a broad first search and a gene-specific second search, supplemented by reference checking. We included studies describing bona fide TSGs in CMM with promoter CpG-island hypermethylation in which inactivating mechanisms were reported. We extracted data about protein role, pathway, experiments conducted to meet the bona fide criteria and hallmarks of cancer acquired by TSG inactivation. A total of 24 studies were included, describing 24 bona fide TSGs silenced by promoter CpG-island hypermethylation in CMM. Their effect on cell proliferation, apoptosis, growth, senescence, angiogenesis, migration, invasion or metastasis is also described. These data give further insight into the role of TSGs in the progression of CMM. Full article

(This article belongs to the Special Issue Molecular Biology, Immune Surveillance and Progressive Disease: New Insights in Melanoma Research)

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