Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know

Bol, Kalijn F.; Donia, Marco; Heegaard, Steffen; Kiilgaard, Jens Folke; Svane, Inge Marie

doi:10.3390/ijms21155231

Cited by 18 publications

(22 citation statements)

References 98 publications

(143 reference statements)

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“…In this study, none of the CM harbored an activating hotspot mutation in GNAQ or GNA11. These findings are congruent with other studies analyzing mutations in CM [ 15 , 46 ]. BRAF and NRAS mutations are extremely rare in UM [ 37 ].…”

Section: Discussionsupporting

confidence: 93%

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

Poppelen

Ipenburg

Bosch

et al. 2021

IJMS

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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.

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Section: Discussionsupporting

confidence: 93%

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

Poppelen

Ipenburg

Bosch

et al. 2021

IJMS

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“…Patients in clusters 1/2 also exhibit 6p gain, which is associated with a better prognosis, while chromosome 6 status is normal in cluster 3/4 subjects [5]. Amplification or gain of chromosome 8 (clusters 4 and 2/3, respectively) has been shown to accelerate metastatic disease [22,[25][26][27].…”

Section: Chromosomal Statusmentioning

confidence: 99%

Development of new therapeutic options for the treatment of uveal melanoma

et al. 2021

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Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Important cytogenetic and genetic risk factors for the development of UM include chromosome 3 monosomy, mutations in the guanine nucleotide-binding proteins GNAQ/GNA11, and loss of the BRACA1-associated protein 1 (BAP 1). Most primary UMs are treated conservatively with radiotherapy, but enucleation is necessary for large tumours. Despite the effectiveness of local control, up to 50% of UM patients develop metastasis for which there are no effective therapies.Attempts to utilize the targeted therapies that have been developed for the treatment of other cancers, including a range of signal transduction pathway inhibitors, have rarely produced significant outcomes in UM. Similarly, the application of immunotherapies that are effective in cutaneous melanoma to treat UM have also been disappointing. Other approaches that have been initiated involve proteasomal inhibitors and histone deacetylase inhibitors that are approved for the treatment of other cancers. Nevertheless, there have been occasional positive outcomes from these treatments in UM. Moreover, combination approaches in UM have also yielded some positive developments. It would be valuable to identify how to apply such therapies efficiently in UM, potentially via individualized tumour profiling. It would also be important to characterize UM tumours to differentiate the potential drivers of progression from those in other types of cancers.The recent identification of novel kinases and metastatic genes in UM tumours makes the development of new UM-specific treatments feasible. Accepted ArticleThis article is protected by copyright. All rights reserved A) Uveal Melanoma: Background and risk factors Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and represents ~5 % of melanoma diagnoses in the US annually [1-3]. UM originates from ocular melanocytes with 85% of cases arising from the choroid region and the remainder from the ciliary body and iris [4]. The prognosis in UM is poor, in particular because around 50% of patients develop metastatic disease. Hepatic metastases occur in up to 90% of individuals, followed by metastases in lung and bones, and after establishment of metastatic disease the median survival time is only 4-5 months [5]. At the time of diagnosis, systemic metastases are reported in only 3%of patients, but it is likely that micro-metastases have already developed in many cases [6,7].Currently there are no effective systemic drug therapies for primary or metastatic UM [8,9].The median age at diagnosis is 62 years and the incidence of UM in males and females, and whether there is right or left eye involvement, is similar [10]. Underlying risk factors for UM include melanocytosis, melanocytoma, neurofibromatosis and the presence of atypical nevi [11][12][13][14]. Race is also a significant risk factor with a 150-fold greater incidence in fair-skinned over dark-skinned populations [15]. The incidence of UM in European countries varies wi...

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“…22,41 These BRAF mutations are also found in up to 52% of cutaneous melanomas, 18,26,42,43 represent 50% of the mutations found in benign melanocytic nevi, 44,45 but have never been reported in uveal melanoma. [46][47][48][49] BRAF-mutant conjunctival melanomas seem to be characterized by a more aggressive…”

Section: Genetic and Epigenetic Changes In Conjunctival Melanomamentioning

confidence: 99%

“…NRAS mutations are present in 6.4% (n=36) of conjunctival melanomas and up to 28% of cutaneous melanomas (Table 1) 11,16,20,26,27,35,37,39 and are not found in uveal melanomas. 49,52 In 88.9% (n = 32) of cases, NRAS mutations are located in codon 61, where a glutamine (Q) is substituted either by an arginine (R) in 40.6% (n=13) of them, by a lysine (K) in 15.6% (n=5) of them, by a histidine (H) in 9.4% (n=3) of them or by a leucine (L) in 9.4% (n=3) of them. In 25% (n=8) of the reported cases, the amino acid substitution at codon 61 has not been characterized.…”

mentioning

confidence: 99%

<p>Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies</p>

Gkiala¹,

Palioura²

2020

OPTH

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Purpose: To present the molecular mechanisms involved in the pathogenesis of conjunctival melanoma (CM) and review the existing literature on targeted molecular inhibitors as well as immune checkpoint inhibitors for the management of locally advanced and metastatic disease. Methods: A comprehensive review of the literature was performed using the keywords "conjunctival melanoma", "immune checkpoint inhibitors", "BRAF inhibitors", "MEK inhibitors", "CTLA4 inhibitors", "PD1 inhibitors", "c-KIT mutations", "BRAF mutations", "NRAS mutations", "dabrafenib", "trametinib", "vemurafenib", "ipilimumab", "pembrolizumab", and "nivolumab". A total of 250 articles were reviewed and 120 were included in this report. Results: Mutations of mediators in the MAP kinase pathway, such as RAS, BRAF, MEK and ERK, and mutations of the PI3K/AKT/mTOR pathway play a major role in the pathogenesis of conjunctival melanoma. In addition, alterations of c-KIT, NF1, TERT, chemokine receptors as well as chromosomal copy number alterations and micro RNAs are thought to have a causative association with CM development. Targeted molecular inhibitors, such as BRAF and MEK inhibitors, are currently being implemented in the therapy of BRAF-mutated CM. Furthermore, immune checkpoint PD-1 and CTLA4 inhibitors with favorable clinical outcomes in the treatment of cutaneous melanoma have increased recurrence-free survival and reduced metastatic spread in CM cases. Conclusion: The complex molecular mechanisms that contribute to the development of CM can be targeted both by molecular inhibitors of oncogenic pathways as well as immune checkpoint inhibitors in order to halt progression of the disease and increase survival.

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Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know

Cited by 18 publications

References 98 publications

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

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

Development of new therapeutic options for the treatment of uveal melanoma

<p>Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies</p>

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