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

Wróblewska, Joanna; Dias‐Santagata, Dora; Ustaszewski, Adam; Wu, Cheng-Lin; Fujimoto, Masakazu; Selim, M. Angélica; Biernat, Wojciech; Ryś, Janusz; Marszałek, Andrzej; Hoang, Mai P.

doi:10.3390/cells10092216

Cited by 11 publications

(5 citation statements)

References 53 publications

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“…In a large cohort of mucosal melanomas, 3% of AMs showed BRAF , 10% showed NRAS , and 19% showed KIT mutations. This study analyzed a subset of cases by Sanger sequencing, and others by next-generation sequencing (NGS); and proposed NRAS mutation as a predictor of worse survival, independent of stage in all mucosal melanomas ( 46 ). Those being mentioned, as a limitation of this study, we had a limited number of cases, impeding a correlation analysis between mutational status and prognostic data.…”

Section: Discussionmentioning

confidence: 99%

Braf, nras, kit, tert, gnaq/gna11 mutation profile and histomorphological analysis of anorectal melanomas: a clinicopathologic study

Taşkin¹,

Sarı²,

Yılmaz³

et al. 2022

TJPATH

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Objective: Primary anorectal melanomas (AMs) are uncommon neoplasms with aggressive behavior. Molecular profile and clinicopathologic features of AMs are still not well established. In this study, we aimed to investigate BRAF, NRAS, KIT, TERT, and GNAQ/GNA11 mutation status and clinicopathologic features of AMs. Material and Method: All diagnostic slides of 15 AMs were reviewed. Histopathological and follow-up information were documented. Mutations in exon 15 of the BRAF gene; exons 2 and 3 of the NRAS gene; exons 9, 11, 13, 17, and 18 of the KIT gene; and exons 4 and 5 of the GNAQ/GNA11 genes and mutations in the promoter region of the TERT gene (chr.5, 1,295,228C>T and 1,295,250C>T) were analyzed. Results: BRAF (V600E) and KIT (V555I and K642E) mutations were observed in one (7%) and two cases (14%), respectively. NRAS, TERT and GNAQ/GNA11 mutations were not detected. The mean age was 65. Patients presented with rectal mass, rectal bleeding, pain, and weight loss. 73% of the lesions were macroscopically polypoid. The most common tumor cell type was epithelioid. Mean tumor thickness was 10.4 mm. One third of the cases lacked pigmentation. In situ melanoma was present in one third of the cases. Among 14 patients with follow-up data, 12 succumbed to disease. The mean overall survival was 36 months. Conclusion: AMs are uncommon tumors with dismal survival, usually occurring in the elderly in various gross and microscopic appearances. In terms of molecular profile, BRAF and KIT mutations are rarely detected. Profiling of larger cohorts is required to elucidate the pathogenesis and to identify potential molecular indicators that may contribute to the development of individualized targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Braf, nras, kit, tert, gnaq/gna11 mutation profile and histomorphological analysis of anorectal melanomas: a clinicopathologic study

Taşkin¹,

Sarı²,

Yılmaz³

et al. 2022

TJPATH

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“…Interestingly, while being resistant to vemurafenib in vitro, the ZNF767-BRAF fusion showed in vitro and in vivo response to MEK inhibitor alone or combined with either Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) or cyclin-dependent kinases (CDK) 4/6 inhibitors [ 19 ]. The distribution of BRAF and NRAS mutation varies according to geographic regions, as observed in cutaneous melanoma, and might explain the better survival observed among European patients in comparison with patients from North America and Asia [ 20 ].…”

Section: Genomic Profilingmentioning

confidence: 99%

Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review

Indini

Roila

Grossi

et al. 2021

IJMS

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Mucosal melanoma is a rare and aggressive subtype of melanoma. Unlike its cutaneous counterpart, mucosal melanoma has only gained limited benefit from novel treatment approaches due to the lack of actionable driver mutations and poor response to immunotherapy. Over the last years, whole-genome and exome sequencing techniques have led to increased knowledge on the molecular landscape of mucosal melanoma. Molecular studies have underlined noteworthy findings with potential therapeutic implications, including the presence of KIT mutations, which are potential targets of tyrosine kinase inhibitors currently in use in the clinic (imatinib), but also SF3B1 mutation, CDK4 amplifications, and CDKN2A gene deletions, which are presently under investigation in clinical trials. Recent results from a pooled analysis of patients with mucosal melanoma treated with immunotherapy have suggested that the combination of immune checkpoint inhibitors might improve survival outcomes in this subset of patients, as compared with single-agent immunotherapy. However, these results are not confirmed across different studies, and combo-immunotherapy correlates with a higher rate of adverse events. In this review, we describe the clinical, biological, and genetic features of mucosal melanoma. We also provide an update on the results of approved systemic treatment in this setting and overview the therapeutic strategies currently under investigation in clinical trials.

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“…Frequently mutated genes in MM are as follows: NRAS (14%–30%), BRAF (5%–16%), NF1 (16%), KIT (5%–15%), SF3B1 (12%), TP53 (8.9%) and SPRED1 (7%). 14 Mutations in BRAF and NRAS observed in MM are substantially different from those occurring in CM. 4 , 7 , 15 BRAF mutation was present in 26% of patients with vulvar and vaginal melanoma; however, only half of them were V600 mutations, which significantly reduces the effectiveness of BRAF and MEK inhibitors therapy typically used in CM.…”

Section: Introductionmentioning

confidence: 98%

“…Mucosal melanoma shows increased genomic instability and lower rates of somatic mutations in comparison with CM. Frequently mutated genes in MM are as follows: NRAS (14%–30%), BRAF (5%–16%), NF1 (16%), KIT (5%–15%), SF3B1 (12%), TP53 (8.9%) and SPRED1 (7%) 14 . Mutations in BRAF and NRAS observed in MM are substantially different from those occurring in CM 4,7,15 .…”

Section: Introductionmentioning

confidence: 99%

Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells

Simiczyjew,

Wądzyńska,

Kot

et al. 2023

J Cellular Molecular Medi

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Mucosal melanoma (MM) is a very rare and aggressive type of cancer for which immunotherapy or targeted therapy such as BRAF/MEK inhibitors, used in cutaneous melanoma, usually fail. Due to our earlier experience showing the high effectiveness of epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) inhibitors in reducing the activation of the MAPK and PI3K/AKT signalling pathways, we aim to test whether these drugs would also be effective for mucosal melanoma. Cells representing two commercially available mucosal melanoma cell lines (GAK and HMVII) and one cell line obtained from a patient's vaginal melanoma were treated with MET or EGFR inhibitors, or combinations of these agents. The dual‐inhibitor treatment strategy resulted in a decrease of cell proliferation, migration and invasion. Moreover, combinations of inhibitors led to reduction of pEGFR/EGFR and pMET/MET ratio and downregulation of PI3K/AKT and MEK/ERK1/2‐based signalling pathways. Our findings indicate a potential therapeutic strategy based on EGFR and MET inhibitors in mucosal melanoma, which should be further evaluated in vivo and in clinical experiments. They also suggest that targeting multiple receptor tyrosine kinases may block signalling crosstalk and possibly delay the appearance of resistance to kinase inhibitors in mucosal melanoma cells.

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

Cited by 11 publications

References 53 publications

Braf, nras, kit, tert, gnaq/gna11 mutation profile and histomorphological analysis of anorectal melanomas: a clinicopathologic study

Braf, nras, kit, tert, gnaq/gna11 mutation profile and histomorphological analysis of anorectal melanomas: a clinicopathologic study

Molecular Profiling and Novel Therapeutic Strategies for Mucosal Melanoma: A Comprehensive Review

Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells

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