Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features

Merkel, Emily A.; Gerami, Pedram

doi:10.1038/labinvest.2016.147

Cited by 64 publications

(66 citation statements)

References 60 publications

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“…Up to date, promising recurrent regions of gains and losses were identified (5) and confirmed by several investigations (4,7,8), in particular amplified portions of HSA 12q and 5p, which encode for genes as CDK4 and TERT, respectively (7). In addition, CCND1, KIT, and VEGFRA were proposed by a recent review (10) as targets for future investigations. hMMs represent only the 1.3% of all reported melanomas (1) and they may arise from different sites, as head-and-neck, female genital tract, and anal/rectal mucosa, with a respective 5 years survival rate of 31.7, 11.4, and 19.8%, while cMM has a 5 years survival rate of 80.8% (1).…”

Section: Introductionmentioning

confidence: 67%

“…Among the genes related to cell proliferation and mitosis, GRHL2, a transcription factor able to bind the promoter region of TERT, was found to be gained. Although TERT is one of the most frequently involved genes in human non UV-induced melanomas (7,10) it has never been found amplified in COMs. However, the gain of GRHL2 suggests that TERT expression may play a role in COMs.…”

Section: Discussionmentioning

confidence: 99%

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Array Comparative Genomic Hybridization Analysis Reveals Significantly Enriched Pathways in Canine Oral Melanoma

et al. 2019

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Human Mucosal Melanoma (hMM) is an aggressive neoplasm of neuroectodermal origin with distinctive features from the more common cutaneous form of malignant melanoma (cMM). At the molecular level, hMMs are characterized by large chromosomal aberrations rather than single-nucleotide mutations, typically observed in cMM. Given the scarcity of available cases, there have been many attempts to establish a reliable animal model. In pet dogs, Canine Oral Melanoma (COM) is the most common malignant tumor of the oral cavity, sharing clinical and histological aspects with hMM.To improve the knowledge about COM's genomic DNA alterations, in the present work, formalin-fixed, paraffin-embedded (FFPE) samples of COM from different European archives were collected to set up an array Comparative Genomic Hybridization (aCGH) analysis to estimate recurrent Copy Number Aberrations (CNAs). DNA was extracted in parallel from tumor and healthy fractions and 19 specimens were successfully submitted to labeling and competitive hybridization. Data were statistically analyzed through GISTIC2.0 and a pathway-enrichment analysis was performed with ClueGO. Recurrent gained regions were detected, affecting chromosomes CFA 10, 13 and 30, while lost regions involved chromosomes CFA 10, 11, 22, and 30. In particular, CFA 13 showed a whole-chromosome gain in 37% of the samples, while CFA 22 showed a whole-chromosome loss in 25%. A distinctive sigmoidal trend was observed in CFA 10 and 30 in 25 and 30% of the samples, respectively. Comparative analysis revealed that COM and hMM share common chromosomal changes in 32 regions. MAPK-and PI3K-related genes were the most frequently involved, while pathway analysis revealed statistically significant perturbation of cancer-related biological processes such as immune response, drug metabolism, melanocytes homeostasis, and neo-angiogenesis. The latter is a new evidence of a significant involvement of neovascularization-related pathways in COMs and can provide the rationale for future application in anti-cancer targeted therapies.

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Section: Introductionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Array Comparative Genomic Hybridization Analysis Reveals Significantly Enriched Pathways in Canine Oral Melanoma

et al. 2019

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“…Since COM shares some features with its human counterpart such as histologic phenotype, tumour genetics and clinical behavior, it is increasingly under evaluation as a spontaneous animal model of human non‐UV induced/sun‐protected sites melanomas, especially acral and mucosal melanomas . Some of the mechanisms of mutagenesis for human melanoma arising in sun‐protected sites were recently evaluated, and early chromosomal instability in CCND1, KIT, PDGFRA and TERT was the most common genetic alteration reported . In particular, chromosomal instability surrounding Cyclin D1 is the most frequently described in human acral and mucosal melanomas where copy number gains and amplification are detected in 31 to 45% of cases .…”

Section: Introductionmentioning

confidence: 99%

Cyclin D1 immunohistochemical expression and somatic mutations in canine oral melanoma

Zamboni

Brocca

Ferraresso

et al. 2019

Vet Comparative Oncology

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Canine oral melanoma (COM) is the most frequent tumour with oral localization in dogs. Copy number gains and amplifications of CCND1, a gene coding for Cyclin D1, are the most frequent chromosomal aberrations described in human non-UV induced melanomas. Twenty-eight cases of COM were retrieved from paraffin-blocks archives. A total of 4 μm thick sections were immunostained with an antibody against human Cyclin D1 and Ki-67. Cyclin D1 and Ki-67 expressions were scored through two counting methods. DNA was extracted from 20 μm thick sections of formalin-fixed paraffin-embedded blocks. Pathological and surrounding healthy tissue was extracted independently. Cyclin D1 immunolabelling was detected in 69% (18/26) while Ki-67 was present in 88.5% (23/26) of cases. Statistical analysis revealed correlation between two counting methods for Cyclin D1 (r = 0.54; P = .004) and Ki-67 (r = 0.56; P = .003). The correlation found between Ki-67 and Cyclin D1 indexes in 16/26 cases labelled by both antibodies (r = 0.7947; P = .0002) suggests a possible use of Cyclin D1 index as prognostic marker. Polymerase chain reaction analysis on CCND1 coding sequence revealed the presence of nine somatic mutations in seven samples producing synonymous, missense and stop codons. Since none of the single-nucleotide polymorphisms was found to be recurrent, it is suggested that overexpression of Cyclin D1 may be the consequence of alterations of CCND1 upstream regions or other genetic aberrations not detectable with the methodology used in this study. Future studies are needed to verify the potential use of Cyclin D1 index as prognostic indicator and to highlight the molecular events responsible for Cyclin D1 overexpression in COMs. K E Y W O R D S CCND1, Cyclin D1, dog, immunohistochemistry, melanoma

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“…Melanomas arising on acral surfaces (defined as the glabrous skin of the palms and soles as well as the nail apparatus) are relatively rare (~1.5%‐3% of melanoma cases) yet confer comparatively lower survival rates vs other types of cutaneous malignant melanomas (CMMs). Interestingly, most acral melanomas arise on relatively sun‐protected skin, with some studies suggesting that the heel of the foot is the most common site . As such, genetic damage from ultraviolet radiation (UVR) is thought to be less of a contributor to acral melanoma formation .…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, most acral melanomas arise on relatively sun‐protected skin, with some studies suggesting that the heel of the foot is the most common site . As such, genetic damage from ultraviolet radiation (UVR) is thought to be less of a contributor to acral melanoma formation . Indeed, genetic studies have shown that acral melanomas carry significantly less of a UVR mutation burden and possess acral‐melanoma‐specific driver mutations, which together suggest an alternative pathogenesis of acral melanoma vs other types of CMM.…”

Section: Introductionmentioning

confidence: 99%

Depletion of primary cilium in acral melanoma

et al. 2019

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Background A eukaryotic cell's primary cilium (PC) is critical for cell signaling, migration and homeostasis. Primary cilium dysfunction has been demonstrated in several malignancies, but whether primary cilia loss occurs in acral melanoma has remained unknown. To address this, we examined the ciliation index (% melanocytes containing a PC) of patient‐derived, biopsy‐proven acral melanoma and compared these to benign acral nevi. Methods We generated a pilot initiative study that included six acral melanomas and seven acral nevi derived from the foot. Using fluorescent immunohistochemistry, we calculated ciliation indexes of Sox10+ melanocytes. Results Average ciliation index for acral nevi was 74.0% (SE of the mean [SEM] 3.3%) vs 9.3% for acral melanoma (SEM 5.7%), finding a statistically significant difference between the groups (P‐value <.001, two tailed t test). Conclusion The data show a significant loss of primary cilia in malignant acral melanoma vs benign acral nevi, suggesting that cilia may play an important role during acral melanoma formation. Our data, which should be validated by a larger study with longer follow‐up period, suggest that examining ciliation index may be a useful diagnostic test when distinguishing benign acral nevi from melanoma.

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Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features

Cited by 64 publications

References 60 publications

Array Comparative Genomic Hybridization Analysis Reveals Significantly Enriched Pathways in Canine Oral Melanoma

Array Comparative Genomic Hybridization Analysis Reveals Significantly Enriched Pathways in Canine Oral Melanoma

Cyclin D1 immunohistochemical expression and somatic mutations in canine oral melanoma

Depletion of primary cilium in acral melanoma

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