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

2020 ◽  
Vol 21 (15) ◽  
pp. 5231 ◽  
Author(s):  
Kalijn Fredrike Bol ◽  
Marco Donia ◽  
Steffen Heegaard ◽  
Jens Folke Kiilgaard ◽  
Inge Marie Svane
Keyword(s):  
Uveal Melanoma ◽  
Current Practice ◽  
Clinical Care ◽  
Primary Melanoma ◽  
Ocular Melanoma ◽  
Conjunctival Melanoma ◽  
Medical Oncologist ◽  
Braf Mutations ◽  
Genetic Biomarkers ◽  
Genetic Features

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.

scholarly journals Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing

2020 ◽  
Vol 22 (1) ◽  
pp. 336
Author(s):  
Natasha M. van Poppelen ◽  
Daniël P. de Bruyn ◽  
Tolga Bicer ◽  
Rob Verdijk ◽  
Nicole Naus ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Gene Mutations ◽  
Ocular Melanoma ◽  
Conjunctival Melanoma ◽  
Iris Melanoma ◽  
Uveal Tract ◽  
Tert Promoter ◽  
Promoter Gene ◽  
Frequent Mutations ◽  
Genetic Profiles

Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. These malignancies derive from melanocytes in the uveal tract or conjunctiva. The genetic profiles of these different entities differ from each other. In uveal melanoma, GNAQ and GNA11 gene mutations are frequently found and prognosis is based on mutation status of BAP1, SF3B1 and EIF1AX genes. Iris melanoma, also originating from the uvea, has similarities to the genetic makeups of both posterior uveal melanoma (UM) and conjunctival melanoma since mutations in GNAQ and GNA11 are less common and genes involved in conjunctival melanoma such as BRAF have been described. The genetic spectrum of conjunctival melanoma, however, includes frequent mutations in the BRAF, NRAS and TERT promoter genes, which are found in cutaneous melanoma as well. The BRAF status of the tumor is not correlated to prognosis, whereas the TERT promoter gene mutations are. Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma. Tissue material is needed to classify ocular melanoma in the different subgroups, which creates a need for the use of noninvasive techniques to prognosticate patients who underwent eye preserving treatment.

scholarly journals Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression

2011 ◽  
Vol 104 (3) ◽  
pp. 464-468 ◽  
Author(s):  
J Lin ◽  
Y Goto ◽  
H Murata ◽  
K Sakaizawa ◽  
A Uchiyama ◽  
...  
Keyword(s):  
Primary Melanoma ◽  
Braf Mutations ◽  
Selection Of

Metaanalysis of BRAF mutations and clinicopathologic characteristics in primary melanoma

2015 ◽  
Vol 72 (6) ◽  
pp. 1036-1046.e2 ◽  
Author(s):  
Soo Young Kim ◽  
Soo Nyung Kim ◽  
Hyung Jin Hahn ◽  
Yang Won Lee ◽  
Yong Beom Choe ◽  
...  
Keyword(s):  
Primary Melanoma ◽  
Braf Mutations ◽  
Clinicopathologic Characteristics

Prognostic value of BRAFV600 mutations in melanoma patients after resection of metastatic lymph nodes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8540-8540
Author(s):  
Philippe Saiag ◽  
Stephanie Moreau ◽  
Philippe Aegerter ◽  
Daphne Bosset ◽  
Christine Longvert ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Prognostic Value ◽  
Proportional Hazards ◽  
Univariate Analysis ◽  
Primary Melanoma ◽  
Stage Iv ◽  
Cox Proportional Hazards ◽  
Stage Iii ◽  
Rank Test ◽  
Braf Mutations

8540 Background: Prognosis of AJCC stage III melanoma is heterogeneous. BRAFV600 mutations are frequent in melanomas. BRAFV600-targeted therapy has dramatic, but often transitory, efficacy in stage IV patients (pts). We aimed to determine for the first time the prognostic value of BRAFV600 mutations and other known prognostic criteria in stage III pts with sufficient nodal invasion. Methods: We searched all pts with cutaneous melanoma who had radical lymphadenectomy in our institution between 1/1/00 and 15/6/10 and included those with a nodal deposit >2 mm. BRAFV600 mutations were detected by DNA sequencing and pyrosequencing in formalin-fixed nodal samples containing >60% melanoma cells. Samples were considered mutated when >15% of DNA was positive. Endpoints were overall survival (OS) and distant metastasis free survival (DMFS). 92 patients had to be included to demonstrate a doubling of OS in patients without (40 months (m)) and with BRAFV600 mutation (20 m). Log-rank test and multivariate Cox proportional hazards regression model were used. Results: 105 consecutive pts were included, with 72% prospectively followed-up pts. BRAFV600 mutations (E: 83%; K: 14% of pts) were detected in 40% of pts. Median follow-up was 19 m (range: 3-139). Death occurred in 83% and 60% of pts with and without BRAF mutations, respectively, with median OS of 1.4 and 2.8 years. Pts’ age, primary melanoma ulceration, number of invaded nodes, AJCC staging, and BRAF status influenced OS and DMFS in the univariate analysis. The multivariate analysis showed the major prognostic role of BRAF status and of the number of invaded nodes (table). Conclusions: Provided our findings are independently replicated, BRAFV600 status should be used to stage melanoma pts with nodal metastasis. Our results also help to plan adjuvant trials with BRAFV600-targeted therapy in such patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies. [Table: see text]

Analysis of BRAF mutations in circulating tumor cells selected by size from patients with melanoma and comparision to the primary tumor.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21014-e21014
Author(s):  
Janine Wechsler ◽  
Naoual Benali-Furet ◽  
Fei Ye ◽  
Marie-Françoise Avril ◽  
Francoise Boitier ◽  
...  
Keyword(s):  
Primary Tumour ◽  
Primary Melanoma ◽  
Melanoma Cells ◽  
Molecular Target ◽  
Tumour Cells ◽  
Benign Lesions ◽  
Braf Mutations ◽  
Tumour Removal ◽  
Healthy Donors ◽  
The Mean

e21014 Background: The efficacy of anti-BRAF therapies in patients with melanoma has emphasized the need to identify BRAF mutations in the tumour. As circulating tumour cells (CTC) derive from the primary tumour (PT), their analysis may represent a non-invasive tool to follow the molecular-target in blood after tumour removal. Methods: This prospective study included 26 patients: 24 patients had confirmed melanoma, 2 patients had benign lesions (1 naevus and 1 pyogenic granuloma). Blood samples were taken at time of the PT surgical excision; 12 healthy donors were included as controls. The 24 patients, 13 females and 11 males, had invasive melanoma (13 superficial spreading melanoma, 7 nodular melanoma, 1 lentigo malignant melanoma, 1 desmoplastic melanoma, 2 unclassified melanoma.). The mean thickness was 7.8 mm. Cytology, immunophenotyping and analysis of BRAF mutations on exon 15 were performed comparatively in primary tumour and CTC from the same patient. CTC were selected by the ScreenCell method, a single-use innovative system to isolate rare tumour cells through a filter-membrane on the basis of their size. Nucleic acids DNA/RNA were extracted from live CTC after filtration. Results: Isolated CTC and microemboli were found in 21/24 patients and were found comparable to the primary melanoma cells. No CTC was found in 10 healthy donors and 2 patients with benign lesions. The mean number of CTC was 2 CTC per ml, the maximum was 4 CTC and 7 microemboli per ml. Malignancy of CTC was assessed on classic criteria: cell size larger than 15 microns, nucleo-cytoplasmic ratio > 0.5, presence of clusters composed of pleomorphic cells. CTC were positively immunostained either by S-100 or MART1/melanA or HMB45 antibodies; 4 patients were studied for BRAF mutations in both melanoma and CTC. The results (2 negative and 2 positive) were concordant in primary melanoma cells and CTC. The V600E-BRAF mutation was found in the 2 positive cases. Conclusions: The ScreenCell method of CTC selection by size allows to detect BRAF mutations in CTC of patients with melanoma. This simple method could be proposed to follow the molecular-target during the course of evolution and treatment after tumour removal.

Analysis of BRAF, NRAS, cKIT, and EGFR alterations in melanoma lung metastases.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19033-e19033
Author(s):  
Alessandra Ulivieri ◽  
Giuseppe Cardillo ◽  
Liborio Manente ◽  
Andrea Petricca Mancuso ◽  
Leonardo Vigna ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Direct Sequencing ◽  
Primary Melanoma ◽  
High Response Rate ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Fish Analysis ◽  
Braf Mutations ◽  
Curative Intent ◽  
Free Survival

e19033 Background: About 25% of pts will eventually develop lung metastases from primary melanoma. Activating mutations in BRAF, NRAS, CKIT and EGFR genes are involved in melanoma progression. Trials with drugs targeting oncogenic BRAF in melanoma have shown that a V600E mutation may identify a subgroup of pts with a high response rate. Methods: We analysedtheprevalence of BRAF, NRAS and CKIT mutations by direct sequencing and of EGFR copy number alterations by FISH, in pts affected by melanoma lung metastases, and explored their correlation with lung metastasis-free survival (LMFS) and post surgical progression-free survival (psPFS). Results: Over 10 years, 33 cases of pts with melanoma lung metastases were diagnosed at our institution, of which 22 underwent surgery with curative intent. The mean age was 64 years, and 19 (57.5%) were male. 51% carried a BRAF V600E mutation while 18% had a NRAS codon 61 mutation. The two events were mutually exclusive. No alterations were observed in exon 11 of the CKIT gene. FISH analysis indicated an EGFR low amplification in 3 cases and chromosome 7 polysomy in 13 cases. The presence of a BRAF V600E mutation was associated with a longer LMFS (median 6.1 vs 4.4 years, p<0.05), but it had no impact on psPFS (26.9 vs 29.6 months, p=0.6). NRAS mutations were associated with a reduction in both LMFS (3.7 years vs 4.7 years, p = 0.008) and, more significantly, in psPFS (12,5 months vs 41,1 months, p = 0.005; hazard ratio, 2.7). Conclusions: The frequency of mutations in BRAF (51%) and NRAS (18%) observed in lung metastatic melanomas was similar to the rates reported in other metastatic sites. BRAF mutations don't appear to be related with a more aggressive clinical course, while NRAS might be an independent negative prognostic factor after resection of melanoma lung metastases. The presence of BRAF mutations should be tested in melanoma lung metastases to identify the patients eligible for anti BRAF targeted therapy.

Clinical characteristics of melanoma patients with non-V600E/K BRAF mutations.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20036-e20036 ◽  
Author(s):  
Sasan Nowroozi ◽  
Zhuang Zuo ◽  
Keyur Patel ◽  
Sapna Pradyuman Patel ◽  
Rajyalakshmi Luthra ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Primary Melanoma ◽  
Stage Iv ◽  
Distant Metastases ◽  
Unknown Primary ◽  
Sequencing Analysis ◽  
Superficial Spreading ◽  
Braf Mutations ◽  
Number Of Patients ◽  
Melanoma Patients

e20036 Background: BRAF mutations are found in ~50% of melanoma. V600E/K substitutions are the most common and well-characterized. We analyzed the clinical characteristics of patients with non-V600E/K BRAF mutations. Methods: We identified 38 melanoma patients whose tumor contained a non-V600E/K BRAF mutation and reviewed the clinical characteristics. The sequencing analysis was performed with either pyrosequencing or next generation sequencing assay. Results: 38 patients were identified with non-V600E/K BRAF mutations. Mutations detected in more than 1 patient included V600R (n=14, 37%), K601E (5, 13%), G469E (3, 8%); L597S (3, 7%), D594G (2, 5%); 11 other mutations were identified in single patients. Median age was 57 yrs; 82% were men; 95% were white. The common primary subtypes were nodular (26%), superficial spreading (24%), unknown primary (21%); no one were acral, mucosal or uveal melanomas. Ten (26%) of 27 with known ulceration status had ulceration, and 3 (7%) of 22 with known mitosis status had < 1 mitosis /mm2. The sites of primary melanoma were located mostly in the head/neck and the trunk (63%), extremities (16%) and unknown primary (21%). The stage at diagnosis was I /II (29%), III (40%), IV (18%) and unknown (13%). Among 33 (87%) patients who ultimately developed distant metastases, 23(67%) had metastasis in the soft tissue/nodes, 21 (63%) in the lung, 9 (24%) in the brain, 7 (21%) in the liver, 6 (16%) in the bone, and 5 (15%) in the adrenal gland. Among patients (n=25) with initial stage I-III melanoma who later developed distant metastasis, the median duration between the time of initial diagnosis and distant metastases was 36 months. Among the 32 (84%) of the patients who developed stage IV melanoma, the median survival from the time of stage IV diagnosis was 18 months. Five patients received vemurafenib treatment, and 2 patients (K601E; T599_V600ins2) had stable disease and 2 patients (L597Q; G466E) had disease progression and 1 lost to follow up. Conclusions: Unexpectedly higher proportion of the patients with non-V600E/K mutant-melanoma had unknown primary melanoma and higher mitotic rate. In a small number of patients who received vemurafenib, the clinical response appears to be low.

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