Molecular profiling of driver events in metastatic uveal melanoma

Karlsson, Jan Ch; Nilsson, Lisa M.; Mitra, Suman; Alsén, Samuel; Shelke, Ganesh Vilas; Sah, Vasu R; Forsberg, Elin; Stierner, Ulrika; All-Eriksson, Charlotta; Einarsdottir, Berglind O.; Jespersen, Henrik; Ny, Lars; Lindnér, Per; Larsson, Erik; Bagge, Roger Olofsson; Nilsson, Jonas A.

doi:10.1038/s41467-020-15606-0

Cited by 116 publications

(162 citation statements)

References 75 publications

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“…Recent findings demonstrated that the deletion of CDKN2a could play an important role in the development and metastatic progression in UM, especially with 8q amplification. However, more studies are needed to clarify better the role of this gene in UM development and biological behavior ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

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Expression of P16INK4a in Uveal Melanoma: New Perspectives

et al. 2020

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Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite sharing the name and similar morphological features with cutaneous melanoma (CM), it is an entirely different neoplasia with a particular genetic background and clinical behavior. CDKN2A is a gene located at chromosome 9p21, encoding for P16INK4a and P14(ARF) proteins, whose role as a tumor suppressor has been clearly defined in many malignant tumors. CDKN2A frequently presents germline mutations in familial CM and epigenetic downregulation in a considerable percentage of sporadic CM. It has been hypothesized that CDKN2A alterations are early events in CM development, playing a central role in the malignant transformation of melanocytes. Alterations of the CDKN2A gene reduce the expression of P16INK4a in most CM subtypes. Immunohistochemical evaluation of P16INK4a is currently used, in association with Ki67 and HMB45, in pathology practice to discriminate between dysplastic nevi and melanoma. On the other hand, CKDN2A is rarely mutated in UM, and the immunohistochemical expression of P16INK4a has only been reported in small case series. We tested P16INK4a expression on paraffin-embedded tissue sections from 9 tissue microarrays (TMAs), built with 2 mm cores derived from 133 uveal melanoma FFPE blocks, collected from 1990 to 2018, and from selected paraffin-blocks of 3 UM liver metastases. The immunohistochemical expression of P16INK4a was assessed with a visual evaluation by light microscopy and then with a digital approach. Both approaches, with an acceptable concordance rate, revealed P16INK4a expression in a large proportion of UM cases and all liver metastases, opening new possibilities of using it in the differential diagnosis between cutaneous and uveal melanoma metastases in cases of unknown primary tumor or patients with two different primary melanomas.

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Section: Discussionmentioning

confidence: 99%

“…It was hypothesized that the monoallelic deletion of CDKN2A and the gain of at least three copies of 8q are early events in UM development. Conversely, acquisition of biallelic loss of CDKN2A and higher amplification of 8q could be relevant in metastatic progression ( 24 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of P16INK4a in Uveal Melanoma: New Perspectives

et al. 2020

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“…In contrast to posterior UM, mutations in BRAF (0–47%) and NRAS have been described in iris melanoma, although the frequency of their presence is unclear, and they might not represent driver mutations ( Table 1 ) [ 44 , 45 , 46 , 47 ]. As the iris is not protected from UV damage, UV-induced mutational signatures have recently been detected in iris melanoma [ 48 , 49 ].…”

Section: Genetic Biomarkers At Initial Diagnosis Of the Primary Tumentioning

confidence: 99%

“…Therefore, experience with the treatment of metastatic iris melanoma is scarce, and little is documented. It could be hypothesized that immune checkpoint inhibitors have possible efficacy, as iris melanoma shows the same UV-induced mutational signatures as cutaneous melanoma [ 48 , 49 ]. As for targeted therapy, it is unknown whether BRAF -mutated iris melanoma responds to BRAF(/MEK) inhibition, as it is not described in the literature.…”

Section: Genetic Biomarkers When Metastatic Disease Is Presentmentioning

confidence: 99%

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

Bol

Donia

Heegaard

et al. 2020

IJMS

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Melanoma of the ocular region (ocular melanoma) comprises about 5% of all patients with melanoma and covers posterior uveal melanoma, iris melanoma, and conjunctival melanoma. The risk of metastasis is much higher in patients with ocular melanoma compared to a primary melanoma of the skin. The subtypes of ocular melanoma have distinct genetic features, which should be taken into consideration when making clinical decisions. Most relevant for current practice is the absence of BRAF mutations in posterior uveal melanoma, although present in some iris melanomas and conjunctival melanomas. In this review, we discuss the genetic biomarkers of the subtypes of ocular melanoma and their impacts on the clinical care of these patients.

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“…The presence of this monosomy is associated with a five-year survival rate of 39%, whereas a 90% five-year survival rate is observed for UM without monosomy 3 [ 58 ]. Interestingly, BRCA1-associated protein-1 (BAP1) is a tumor-suppressor gene placed on chromosome 3, and it is mutated in 47% of primary UM and up to 91% of metastatic UM [ 59 , 60 , 61 , 62 , 63 , 64 ]. The splicing factor 3B subunit 1 (SF3B1) is consistent with disomy 3 and shows more favorable prognosis, although an association with delayed metastases has been reported [ 65 , 66 , 67 ].…”

Section: Prognosis Of Ummentioning

confidence: 99%

Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

Mallone

Sacchetti

Moramarco

2020

Cancers

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Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.

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Molecular profiling of driver events in metastatic uveal melanoma

Cited by 116 publications

References 75 publications

Expression of P16INK4a in Uveal Melanoma: New Perspectives

Expression of P16INK4a in Uveal Melanoma: New Perspectives

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

Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

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