<i><scp>BRAF</scp></i> mutations in conjunctival melanoma: investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions

Larsen, Ann‐Cathrine; Dahl, Christina; Dahmcke, Christina Mackeprang; Lade-Keller, Johanne; Siersma, Volkert; Toft, Peter Bjerre; Coupland, Sarah E.; Prause, Jan Ulrik; Guldberg, Per; Heegaard, Steffen

doi:10.1111/aos.13007

Cited by 95 publications

(92 citation statements)

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“…Information on patient and tumor characteristics, clinical presentation, local recurrence, regional and distant metastases, and cause of death was obtained from clinical patient records, from pathology reports, and by searching the Danish Registry of Pathology and the Danish Register of Causes of Death, as previously described. 2,10 The proliferative index (mitotic rate) was evaluated in slides stained with anti-Ki-67 (Dako Denmark, Glostrup, Denmark) and the percentage of Ki-67-positive cells was assessed. All of the CMs were divided into two groups ( 15% and >15%).…”

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confidence: 99%

MicroRNA Expression Profile in Conjunctival Melanoma

Larsen

Mikkelsen

Borup

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Conjunctival melanoma (CM) is a rare disease associated with considerable mortality. As opposed to cutaneous melanoma, the epigenetic mechanisms involved in the development of CM and other mucosal melanomas (MMs) are unclear. The purpose of this study was to identify tumor-specific and prognostic microRNA (miRNA) in CM and to compare the miRNA profile with that of MM.METHODS. Using microarray analysis (Affymetrix) we determined the miRNA expression profile in 40 CMs compared with 7 normal conjunctival samples. Changes in miRNA expression were associated with T stage, local recurrence, metastasis, and mortality. Furthermore, the expression of six fresh frozen tissue samples of CM was compared with that of four laryngeal and sinonasal MM.RESULTS. Our analysis revealed 24 upregulated and 1 downregulated miRNA in CM; several of these miRNAs have key functions in the pathogenesis and progression of cutaneous melanoma. Additionally, we identified seven upregulated miRNAs specific for stage-T1 and stage-T2 CM, whose expression was associated with increased tumor thickness (P ¼ 0.007), and two upregulated miRNAs (miR-3687 and miR-3916) associated with an increased risk of local recurrence. No stage T3-specific miRNAs were identified.CONCLUSIONS. We identified differentially expressed and potentially prognostic miRNAs in CM. Furthermore, the miRNA expression pattern of CM resembled that in MM. The identification of these differentially expressed miRNAs provides an entry point for future functional studies of miRNAs as prognostic or therapeutic targets in CM and highlights the resemblance between CM, MM, and cutaneous melanoma.Keywords: conjunctiva, melanoma, microRNA, gene expression C onjunctival melanomas (CMs) account for approximately 5% of ocular melanomas and they have an associated mortality of up to 30%. 1,2 Recently, oncogenic mutations in BRAF, NRAS, and KIT have been identified in CM, emphasizing their close genetic resemblance to cutaneous and mucosal melanomas (MMs), and their difference from uveal melanomas (UMs). [2][3][4][5] Owing to the high mortality rate associated with CM and MM, 2,6 there is a need to further identify molecular pathways that drive development and progression. MicroRNAs (miRNAs) are small noncoding RNA molecules that epigenetically regulate gene expression at the posttranscriptional level by either degradation of or translational blockage of target messenger RNAs.7 Deregulation of miRNAs with oncogenic and tumor-suppressive functions have attracted much attention owing to their high prevalence.8 These small miRNA molecules could be used as prognostic or therapeutic targets. A microarray-based miRNA expression profiling platform was therefore used to compare the expression of miRNAs in archived (formalin-fixed, paraffin-embedded [FFPE]) CM and normal conjunctival samples. The miRNA expression pattern in CM was tested for associations with TNM stage, 9 local recurrence, metastasis, and mortality in order to identify prognostic miRNAs. To determine similarities in miRNA expressi...

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MicroRNA Expression Profile in Conjunctival Melanoma

Larsen

Mikkelsen

Borup

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…This similarity, however, should not be seen as a proof of shared origin, since the BRAF mutation may occur in primary conjunctival melanoma as well [21]. This is illustrated by the fact that conjunctival melanomas share a genetic similarity with cutaneous melanomas, rather than with uveal melanomas: BRAF and NRAS mutations that are common in cutaneous melanomas are also seen in conjunctival melanomas, but they are extremely rare in uveal melanomas [22,23].…”

Section: Discussionmentioning

confidence: 99%

Conjunctival Metastasis of a Cutaneous Melanoma

Brouwer

Marinković

Jochems³

et al. 2017

Ocul Oncol Pathol

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Purpose: To report a patient who presented with a conjunctival tumour as a first sign of distant metastasis of cutaneous melanoma. The patient was treated successfully with BRAF/MEK-inhibitors and anti-PD-1 antibodies. Methods: Clinical and histopathological examination of the conjunctival lesion. Results: A 74-year-old man was referred to our hospital with a pigmented conjunctival tumour, 5 months after having been diagnosed with cutaneous melanoma on his right scapula with loco-regional axillary lymph node metastases. The conjunctival lesion was excised and showed a BRAF V600E mutation. Histopathology showed a melanoma with characteristics suspicious for metastasis, as the lesion did not have a relation with the overlying epithelium. Systemic screening showed multiple distant metastases of the cutaneous melanoma in spleen, liver, and bone. Systemic treatment with the combination of a BRAF-inhibitor (dabrafenib) and MEK-inhibitor (trametinib) was started and followed by a switch to an anti-PD-1 antibody (pembrolizumab). Twenty-two months later, the patient is alive and in good clinical health. Conclusion: Conjunctival metastases of cutaneous melanoma may mimic primary conjunctival melanoma. A good medical history and systemic work-up are required to differentiate these diseases. Identification of the proper diagnosis including mutation analysis is crucial, allowing patients to benefit from newly introduced treatment strategies for metastatic cutaneous melanoma.

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“…The BRAF gene encodes B-raf, a serine/threonine kinase that is part of the MAPK pathway, and activating mutations in BRAF have been shown to have a prooncogenic effect that drives cell proliferation as well as tumor progression in melanoma [50]. In up to 50% of CM, activating BRAF mutations can be found [11,16,23]. Another notable mutation that is common in CM is hyperactivated NRAS (in up to 18%) [18].…”

Section: Braf Mutations In CMmentioning

confidence: 99%

“…In particular, the incidence of tumors in locations that are exposed to UV light has increased in both entities, and many authors presume this to be an indicator of phenotypical similarity. In the case of CM, they are predominantly epibulbar tumors developing from PAM, as well as tumors in patients >65 years of age [2,3,14,15,16,17]. …”

Section: Introductionmentioning

confidence: 99%

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Systemic BRAF/MEK Inhibitors as a Potential Treatment Option in Metastatic Conjunctival Melanoma

Mor

Heindl

2016

Ocul Oncol Pathol

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Aim: In this review, we outline similarities between conjunctival and skin melanoma as well as the effectiveness of combined BRAF/MEK inhibition in melanoma, and discuss the applicability of these agents in conjunctival melanoma. Methods: The study provides a PubMed literature review. Results: Conjunctival melanoma and skin melanoma are genetically and phenotypically related. Both tumors typically harbor BRAF mutations in more than 50% of cases. New targeted therapies in metastatic skin melanoma include selective inhibition of BRAF and MEK. Combined BRAF/MEK inhibition has revolutionized the treatment of metastatic skin melanoma, significantly improving patients' prognoses. While these new substances have been investigated extensively in the treatment of skin melanoma, comparable studies in conjunctival melanoma do not exist owing to the rarity of the malignancy. Conclusions: The application of combined BRAF/MEK inhibition in metastatic or unresectable conjunctival melanoma shows great potential for improving patients' prognoses. Future studies are needed to investigate the assumed benefit.

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BRAF mutations in conjunctival melanoma: investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions

Cited by 95 publications

References 30 publications

MicroRNA Expression Profile in Conjunctival Melanoma

MicroRNA Expression Profile in Conjunctival Melanoma

Conjunctival Metastasis of a Cutaneous Melanoma

Systemic BRAF/MEK Inhibitors as a Potential Treatment Option in Metastatic Conjunctival Melanoma

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