7 research outputs found
Tumor Heterogeneity in Uveal Melanomas
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults
with an incidence of 7-10/ million and has a predilection for hematogenous dissemination
to the liver. Despite improvements in diagnosis and treatment of this intraocular
tumor, there has not been a change in survival in the past decades. There is no effective
treatment for liver metastases resulting in tumor-related death in about 45% of UM
patients within 15 years after the initial diagnosis.
Uveal melanoma usually arises ‘de novo’ from melanocytes derived from neural crest
cells that have migrated to the epidermis and uveal tract during embryogenesis. Intraocular
melanoma may arise in the choroid (70-80%), ciliary body (10-20%) and iris
(5-10%). Iris melanomas are the least common and tend to present at a smaller size,
probably because pigmented lesions of the iris are usually visible to the patient. Iris melanomas
can cause drainage angle blockage and secondary elevation of the intraocular
pressure.4 Melanomas located in the ciliary body are associated with a high metastatic
potential. Choroidal melanomas compromise the majority and grow subretinal in a
discoid, dome-shaped or mushroom-shaped pattern.
The diagnosis is based on the clinical appearance of the tumor on ophthalmic examination.
Ancillary tests include (Doppler-) ultrasonography, transillumination, fluorescein
angiography and optical coherence tomography. For the diagnosis of melanoma, biopsy
is reserved for tumors of uncertain origin. Conversely, tumor biopsy gains territory in
vision-sparing therapies for cytogenetic analysis providing risk assessment of metastatic
disease.
Upon diagnosis of the primary tumor, patients are screened for metastases by liver
enzyme tests and liver ultrasound. At time of diagnosis less than 2% of the patients have
detectable metastases
Long Overall Survival After Dendritic Cell Vaccination in Metastatic Uveal Melanoma Patients
Purpose: To assess the safety and efficacy of dendritic cell vaccination in metastatic uveal melanoma. Design: Interventional case series. Methods: We analyzed 14 patients with metastatic uveal melanoma treated with dendritic cell vaccination. Patients with metastatic uveal melanoma received at least 3 vaccinations with autologous dendritic cells, professional antigen-presenting cells loaded with melanoma antigens gp100 and tyrosinase. The main outcome measures were safety, immunologic response, and overall survival. Results: Tumor-specific immune responses were induced with dendritic cell vaccination in 4 (29%) of14 patients. Dendritic cell-vaccinated patients showed a median overall survival with metastatic disease of 19.2months, relatively long compared with that reported in the literature. No severe treatment-related toxicities (common toxicity criteria grade 3 or 4) were observed. Conclusions: Dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Dendritic cell-based immunotherapy is potent to enhance the host's antitumor immunity against uveal melanoma in approximately one third of patients. Compared with other prospective studies with similar inclusion criteria, dendritic cell vaccination may be associated with longer than average overall survival in patients with metastatic uveal melanoma
Metastatic disease in polyploid uveal melanoma patients is associated with BAP1 mutations
PURPOSE. Most of the uvea melanoma (UM) display a near-diploid (normal, ~2N) karyotype with only a few chromosomal changes. In contrast to these simple aberrations 18% of the UM samples show a polyploid character (>2N) and this was associated with an unfavorable prognosis. This study attempts to gain insight in the prognostic value of polyploidy in UM. METHODS. In 202 patients the ploidy status of the UM was determined using cytogenetic analysis, fluorescence-in-situ-hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and/or single nucleotide polymorphism (SNP) array analysis. Immunohistochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) and the mutation hotspots for the SF3B1, EIF1AX, GNAQ, and GNA11 genes was carried out using Sanger sequencing or whole-exome sequencing. RESULTS. Twenty-three patients had a polyploid UM karyotype (11.4%). Patients with a polyploid tumor had larger tumors (15.61 vs. 13.13 mm, P = 0.004), and more often loss of heterozygosity of chromosome 3 (P ¼ 0.003). No difference in occurrence of mutations between polyploid and diploid tumors was observed for BAP1, SF3B1, EIF1AX, GNAQ, and GNA11. Polyploidy did not affect survival (P = 0.143). BAP1 deficiency was the only significant independent prognostic predictor for patients with polyploid tumors, with a 16- fold increased hazard ratio (HR 15.90, P = 0.009). CONCLUSIONS. The prevalence of mutations in the UM related genes is not different in polyploid UM compared with diploid UM. Moreover, similar to patients with diploid UM, BAP1 mutation is the most significant prognostic predictor of metastasis in patients with polyploid UM
Aberrant microRNA expression and its implications for uveal melanoma metastasis
Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1. Still, the mechanisms that drive metastatic spread are largely unknown
Genetics of ocular melanoma: Insights into genetics, inheritance and testing
Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. T
Multi-Modality Analysis Improves Survival Prediction in Enucleated Uveal Melanoma Patients
PURPOSE. Uveal melanoma (UM) is characterized by multiple chromosomal rearrangements
and recurrent mutated genes. The aim of this study was to investigate if copy number
variations (CNV) alone and in combination with other genetic and clinico-histopathological
variables can be used to stratify for disease-free survival (DFS) in enucleated patients with UM.
METHODS. We analyzed single nucleotide polymorphisms (SNP) array data of primary tumors
and other clinical variables of 214 UM patients from the Rotterdam Ocular Melanoma Study
(ROMS) cohort. Nonweighted hierarchical clustering of SNP array data was used to identify
molecular subclasses with distinct CNV patterns. The subclasses associate with mutational
status of BAP1, SF3B1, or EIF1AX. Cox proportional hazard models were then used to study
the predictive performance of SNP array cluster-, mutation-, and clinico-histopathological
data, and their combination for study endpoint risk.
RESULTS. Five clusters with distinct CNV patterns and concomitant mutations in BAP1, SF3B1,
or EIF1AX were identified. The sample’s cluster allocation contributed significantly to
mutational status of samples in predicting the incidence of metastasis during a median of 45.6
(interquartile range [IQR]: 24.7–81.8) months of follow-up (P < 0.05) and vice versa.
Furthermore, incorporating all data sources in one model yielded a 0.797 C-score during 100
months of follow-up.
CONCLUSIONS. UM has distinct CNV patterns that correspond to different mutated driver genes.
Incorporating clinico-histopathological, cluster and mutation data in the analysis results in
good performance for UM-related DFS prediction
Gene expression profiling in uveal melanoma: Two regions on 3p related to prognosis
PURPOSE. Although studies on uveal melanoma (UM) revealed prognostic significance of chromosomal aberrations, they resulted in classification errors in survival prediction.