Conjunctival melanoma: New insights in tumour genetics and immunology, leading to new therapeutic options

Brouwer, Niels J.; Verdijk, Robert M.; Heegaard, Steffen; Marinković, Marina; Esmaeli, Bita; Jager, Martine J.

doi:10.1016/j.preteyeres.2021.100971

Cited by 42 publications

(49 citation statements)

References 314 publications

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“…Although no correlation with prognosis is observed for all mucosal melanomas in the current series, BRAF mutation correlates with worse PFS for sinonasal melanomas when subgroups are analyzed. V600E mutation is observed in mucosal melanomas involving half of the conjunctival melanomas in our study [43]. D594G, G469A and K601E are the frequently observed BRAF variants in mucosal melanomas [34].…”

Section: Discussionsupporting

confidence: 51%

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Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

Wróblewska

Dias‐Santagata

Ustaszewski

et al. 2021

Cells

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Background: The prognostic value of commonly recurrent mutations remains unclear in mucosal melanomas. Methods: Clinicopathologic parameters of 214 cases of mucosal melanomas diagnosed in 1989–2020 in several clinical institutions were analyzed. NRAS, KIT, BRAF, IGF2R and SF3B1 mutational analyses by Sanger sequencing and next generation sequencing-based assay were performed in a subset of cases. Results: Of the triple (BRAF, NRAS, NF1)-negative cases, APC, KIT and KRAS are detected mainly in sinonasal, vulvovaginal and anorectal melanomas, respectively. NRAS, KIT, BRAF, IGF2R and SF3B1 mutations are detected in 19% (37/198), 22% (44/197), 12% (25/201), 16% (22/138) and 15% (20/133) of cases, respectively. In univariate analyses, advanced stage (p = 0.016), 65 years or older (p = 0.048) and presence of ulceration (p = 0.027) are significantly correlated with worse overall survival (OS), respectively. NRAS mutation significantly correlates with worse OS (p = 0.028) and worse melanoma-specific survival (MSS) (p = 0.03) for all cases of mucosal melanomas. In multivariate analyses, NRAS mutation remains as an independent predictor of worse OS (p = 0.036) and worse MSS (p = 0.024). Conclusion: NRAS mutation is a predictor of worse survival, independent of stage in mucosal melanomas. The significance of frequently mutated IGF2R in mucosal melanomas remains unclear.

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Section: Discussionsupporting

confidence: 51%

“…BRAF inhibitors have been shown to significantly lengthen PFS and OS in patients with melanoma harboring BRAF V600 mutations (V600E and V600K) [42,44]. However, BRAF inhibitors target tumors harboring BRAF V600E and not BRAF variants; therefore, other treatment modalities such as RAF inhibitor are currently under study [42][43][44][45].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

Wróblewska

Dias‐Santagata

Ustaszewski

et al. 2021

Cells

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“…Although being anatomically close to the uveal tract, CM is genetically close to cutaneous and mucosal melanomas. Several mutations have been shown to disturb several signalling pathways such as the ‘MAPK’ (mitogen-activated protein kinase, also known as ‘RAS-RAF-MEK-ERK’) pathway and the ‘PI3K-AKT’ (also known as ‘PI3K-AKT-mTOR’) pathway, as well as their regulators, such as NF1 or receptor tyrosine kinases such as KIT [ 12 ]. With TERT promoter mutations, all these abnormalities contribute to the genetic landscape of CM ( Figure 2 ).…”

Section: Biology Of Conjunctival Melanomamentioning

confidence: 99%

“…Taken together, these data support the fact that CMs are a biologically distinct, heterogeneous group of melanomas with a mixed phenotype and features of mucosal melanomas associated with DNA damage induced by chronic UV exposure. Second, even if a clear association between the clinical features or prognosis and the genetic abnormalities have not been established, several results suggest that some mutations could be associated with specific tumorigenesis pathways for some CM subgroups [ 12 , 21 ]. CTNNB1 mutations are more common in nevi-derived CMs, suggesting a pivotal role of the Wnt pathway in their tumorigenesis, whereas the presence of KIT / SF3B1 mutations suggests a mucosal-specific tumorigenic pathway as for other mucosal melanomas [ 11 , 24 , 25 , 26 , 27 ].…”

Section: Biology Of Conjunctival Melanomamentioning

confidence: 99%

“…Despite being anatomically close, CM and uveal melanoma are very different genetically [ 9 , 10 ]. CM shares similarities with both cutaneous melanoma and mucosal melanoma, including their infiltrative nature, their lymphatic and hematogenous spread and the presence of BRAF , NRAS , NF1 and Kit mutations [ 11 , 12 ]. Therefore, like cutaneous melanoma, CM has become a “targetable” malignancy [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

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Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives

Nahon-Estève

Bertolotto

Picard‐Gauci

et al. 2021

Cancers

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Although its incidence has increased over the last decades, conjunctival melanoma (CM) remains a rare but challenging periocular malignancy. While there is currently no recognized standard of care, “no-touch” surgical excision followed by adjuvant treatments is usually recommended. Despite its small size, managing CM is challenging for clinicians. The first challenge is the high risk of tumour local recurrence that occurs in about one third of the patients. The management of locally advanced CM (≥T2) or multiple recurrences may require mutilating surgeries such as orbital exenteration (OE). The second challenge is the metastatic spread of CM that occurs in about one quarter of patients, regardless of whether complete surgical excision is performed or not. This highlights the infiltrative and highly aggressive behaviour of CM. Recently, attention has been directed towards the use of eye-sparing strategies to avoid OE. Initially, wide conservative surgeries followed by customized brachytherapy or radiotherapy have appeared as viable strategies. Nowadays, new biological insights into CM have revealed similarities with cutaneous melanoma. These new findings have allowed clinicians to reconsider the management of locally advanced CM with “medical” eye-sparing treatment as well as the management of metastatic spread. The aim of this review was to summarize the current and future perspectives of treatment for CM based on recent biological findings.

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Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m⁶A RNA methylation in ocular melanoma

Zhuang

et al. 2023

Cancer Communications

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BackgroundDiversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m6A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in‐depth understanding of the crosstalk between histone acetylation and m6A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6A modifications in the regulation of tumorigenesis of ocular melanoma.MethodsHistone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m6A RNA modification level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets and tagmentation, single‐cell sequencing, methylated RNA immunoprecipitation‐sequencing (meRIP‐seq), and m6A individual nucleotide resolution cross‐linking and immunoprecipitation‐sequencing (miCLIP‐seq), were performed to reveal the mechanisms of HDACis on methyltransferase‐like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real‐time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA‐binding protein immunoprecipitation‐qPCR, meRIP‐seq, miCLIP‐seq, and RNA stability assay were adopted to investigate the mechanism by which m6A levels of FAT4 were affected.ResultsFirst, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo‐histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m6A‐YTH N6‐methyladenosine RNA‐binding protein 1‐dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14‐mediated m6A modification in tumorigenesis.ConclusionsThese results demonstrate that HDACis exert anti‐cancer effects by orchestrating m6A modification, which unveiling a “histone‐RNA crosstalk” of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.

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Conjunctival melanoma: New insights in tumour genetics and immunology, leading to new therapeutic options

Cited by 42 publications

References 314 publications

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives

Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m⁶A RNA methylation in ocular melanoma

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Conjunctival melanoma: New insights in tumour genetics and immunology, leading to new therapeutic options

Cited by 42 publications

References 314 publications

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives

Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m6A RNA methylation in ocular melanoma

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Product

Resources

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Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m⁶A RNA methylation in ocular melanoma