Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential

Poppelen, Natasha M. van; Vaarwater, Jolanda; Mudhar, Hardeep Singh; Sisley, Karen; Rennie, I G; Rundle, Paul; Brands, Tom; Bosch, Quincy C. C. van den; Mensink, Hanneke W.; Klein, Annelies de; Kılıç, Emine; Verdijk, Robert M.

doi:10.1016/j.ophtha.2017.12.022

Cited by 46 publications

(38 citation statements)

References 39 publications

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“…6,13,22,23 When the cases are separated on the basis of mutational profile in combination with genetic imbalances, it is apparent that cases 1, 2, and 3 are more akin to UM (M3 and 8qþ with GNAQ, GNA11, and SF3B1 mutations), whereas cases 4, 5, and 6 have mutations of NRAS 12 and TERTp and chromosomal imbalances similar to those of conjunctival melanoma. Iris melanomas equally have been reported to have a mixed genotype, sharing mutations of both cutaneous (BRAF/NRAS) and posterior UM (GNAQ/GNA11 and SF3B1), 29 but the segregation on the basis of mutations is not as distinct as seen here for the orbital melanomas. It is also remarkable that 2 of the cases (cases 5 and 6) have very distinctive profiles, both having 16q-, evidence of i(17q), and a tight focal amplification of 20p, findings that, although similar to conjunctival melanoma, 22 may suggest that primary orbital melanomas have their own characteristic changes.…”

Section: Discussionmentioning

confidence: 44%

Genetic Profiling of Primary Orbital Melanoma

et al. 2019

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Purpose: To analyze the genetic profile of 6 cases of primary orbital melanoma with clinicopathologic correlation. Design: Retrospective noninterventional study to analyze the genetic profile of 6 cases of primary orbital melanoma and to correlate the genetic findings with prognosis and clinicopathologic features. Inclusion criteria were patients with primary orbital melanoma with no evidence of primary eyelid skin, conjunctival, uveal, or remote melanoma at extraocular sites. Participants: The study involved 6 primary orbital melanomas from 6 patients. Four patients were exenterated and 2 had incisional biopsies performed. Methods: Clinical notes and radiologic records were assessed to ascertain clinical tumor behavior. Sections were stained with hematoxylineeosin and exposed to immunohistochemistry for S100, MelA, HMB45, Sox10, and BAP1. Melanoma DNA was exposed to array comparative genomic hybridization to assess gross chromosomal copy number changes. Point mutation assessment and Sanger sequencing were performed for GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX. Main Outcome Measures: These were the presence of gross chromosomal copy number changes and the presence of mutations in GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX; the presence of metastases and time period between diagnosis and death from melanoma; and correlation between the tumor genetic profile and the clinical behavior of the tumor. Results: One of the 6 cases was clinically associated with oculodermal melanocytosis. Of the 6 patients, 3 died of melanoma metastases and 1 of unrelated causes; 2 remain alive at last review. Three of the 6 cases were histologically associated with a benign precursor lesion. All melanomas expressed S100, MelA, HMB45, and Sox10. One patient showed loss of BAP1 nuclear staining. The most frequent chromosomal gains across the 6 cases, in order of frequency, were 6p, 8q, 17q, 6q, and 20p. The most frequently lost regions were 1p, 9p, 16q, and 17p. One patient showed monsomy 3 and gain of 8q (and showed the BAP1 loss). Mutations were found in GNAQ (1 case), GNA11 (1 case), SF3B1 (2 cases), NRAS (2 cases), and pTERT (2 cases). Conclusions: The data point to 2 genetic groups for primary orbital conjunctiva melanoma-like and a uveal melanomaelike group. A larger study would help confirm this suggestion. Ophthalmology 2019;126:1045-1052 ª 2019 by the American Academy of Ophthalmology Primary orbital melanoma accounts for less than 1% of all primary orbital neoplasms. 1 In the largest clinicopathologic series on this subject to date, all 21 cases occurred in white patients, with a mean age at diagnosis of 42 years. Of these cases, 19 (90%) were associated with an orbital blue nevus. Of these 19 cases, 10 cases also showed some form of congenital melanosis (nevus of Ota or ocular melanocytosis). 2 Death from metastatic tumor occurred in 38% of cases, after a mean of 4.5 years follow-up, with liver (88%) and brain (12%) being main targets of metastases. 2 A recent clinical study of 13 cases showed mortality from the ...

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Section: Discussionmentioning

confidence: 44%

Genetic Profiling of Primary Orbital Melanoma

et al. 2019

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“…[6,13] 0 nicht vorkommend, (+) ungewöhnlich, + gelegentlich, ++ häufig, +++ sehr häufig dass nicht jeder melanozytäre Iristumor tatsächlich ein Melanom ist, selbst wenn er vom Aspekt und Verlauf her sehr verdächtig ist und er großenteils der ABCDEF-Regel folgt. Es bleibt bei den melanozytären Proliferationen in der Iris nicht selten das Dilemma der Abgrenzung zwischen "benigne" und "maligne", das sich auch mit zytogenetischen (und histopathologischen) Methoden bisher noch nicht hinreichend auflösen lässt [23]. Es gibt Tumoren im Grenzbereich, die man ohne Festlegung auf "Nävus" oder "Melanom" als "melanozytäre Iristumoren unklaren malignen Potenzials" bezeichnen könnte und sollte [23].…”

Section: Diskussionunclassified

“…Es bleibt bei den melanozytären Proliferationen in der Iris nicht selten das Dilemma der Abgrenzung zwischen "benigne" und "maligne", das sich auch mit zytogenetischen (und histopathologischen) Methoden bisher noch nicht hinreichend auflösen lässt [23]. Es gibt Tumoren im Grenzbereich, die man ohne Festlegung auf "Nävus" oder "Melanom" als "melanozytäre Iristumoren unklaren malignen Potenzials" bezeichnen könnte und sollte [23]. Alternativ könnte man von "melanozytären Grauzonen-Tumoren" sprechen.…”

Section: Diskussionunclassified

Irisnävus oder Irismelanom? Ein progredienter Verlauf über mindestens 43 Jahre

Rohrbach

Süßkind

Bartz‐Schmidt

2018

Klin Monatsbl Augenheilkd

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Section: Introductionunclassified

“…Меланома радужки менее распространена (4-10 %), и в ней, в отличие от меланомы хориоидеи и цилиарного тела, встречаются не только мутации GNAQ или GNA11, но и мутации BRAF, NRAS, что объясняют большей экспозицией радужки облучению ультрафиолетом [14,15]. Таким образом, меланома радужки имеет молекулярный профиль, сравнимый как с меланомой хориоидеи, так и с меланомой кожи, что позволяет рассматривать меланому радужки как отдельный подтип меланомы [15]. Меланома радужки возникает в более молодом возрасте и считается менее агрессивной c более благоприятным прогнозом, чем меланома хориоидеи, тогда как меланома цилиарного тела, наоборот, чаще склонна к метастазированию по сравнению с меланомой хориоидеи [3,14].…”

Section: Introductionunclassified

Molecular and genetic diversity in melanoma of eye

et al. 2018

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Background. Ocular melanoma is the most common cancer of adult eye and is represented by two main subtypes of uveal (UM) and conjunctival (CM) melanoma with distinct clinical (frequency, localization, histology) and genomic features. The objective is to compare molecular and genetic characteristics of tumors in patients with melanoma of the eye. Materials and methods. In this study molecular profiling of 78 tumors including 73 UM (choroidea, ciliar body and iris) and 5 СM, was evaluated. DNA was isolated from tumor cells collected by macrodissection of FEPE sections of tumor biopsies using proteinase K. The following genes were studied by Sanger sequencing: GNAQ, GNA11, KIT, BRAF, NRAS. Results. Mutations in GNAQ and GNA11 were found in 81 % (59/73) of UM, in 42 % (31/73) and 38 % (28/73) of cases correspondently. GNAQ mutations were more frequent in primary UM (63 %), while GNA11 mutations dominated in metastatic UM (42 %). There was а correlation between frequency of GNAQ/GNA11 mutations and histologic type of UM. GNAQ mutations were identified in 55 % of spindle cell UM, while GNA11 mutations were more frequent in epithelioid cell UM (42 %). There were no differences in frequency of GNAQ/GNA11 mutations in UM of patients of different age (younger and elder 50 years). There was no statistically difference in UM patient outcome with GNAQ or GNA11 mutations. We also detected 3 UM with KIT mutations and 2 UM with BRAF mutations. There was no big difference in frequency of «driver mutations» in UM of choroidea, ciliar body and iris. Molecular profiling of conjunctival melanoma (CM) resembles that of cutaneous melanoma of skin: in 3 (60 %) CM BRAF V600E was identified and in 1 (20 %) – NRAS Q61K. Conclusion. Genetic analysis reveals wide diversity of melanoma of eye and is important for it characterization and treatment.

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Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential

Cited by 46 publications

References 39 publications

Genetic Profiling of Primary Orbital Melanoma

Genetic Profiling of Primary Orbital Melanoma

Irisnävus oder Irismelanom? Ein progredienter Verlauf über mindestens 43 Jahre

Molecular and genetic diversity in melanoma of eye

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