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Updated: Jul 11, 2025
Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma
Published on: January 25, 2015
Interdependence of Molecular Lesions That Drive Uveal Melanoma Metastasis
Francesco Reggiani1, Marianna Ambrosio1,2, Michela Croce3
1Laboratory of Gene Expression Regulation, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.
Abstract:
The metastatic risk of uveal melanoma (UM) is defined by a limited number of molecular lesions, somatic mutations (SF3B1 and BAP1), and copy number alterations (CNA): monosomy of chromosome 3 (M3), chr8q gain (8q), chr6p gain (6p), yet the sequence of events is not clear. We analyzed data from three datasets (TCGA-UVM, GSE27831, GSE51880) with information regarding M3, 8q, 6p, SF3B1, and BAP1 status. We confirm that BAP1 mutations are always associated with M3 in high-risk patients. All other features (6p, 8q, M3, SF3B1 mutation) were present independently from each other. Chr8q gain was frequently associated with chr3 disomy. Hierarchical clustering of gene expression data of samples with different binary combinations of aggressivity factors shows that patients with 8q|M3, BAP1|M3 form one cluster enriched in samples that developed metastases. Patients with 6p combined with either 8q or SF3B1 are mainly represented in the other, low-risk cluster. Several gene expression events that show a non-significant association with outcome when considering single features become significant when analyzing combinations of risk features indicating additive action. The independence of risk factors is consistent with a random risk model of UM metastasis without an obligatory sequence.
Insights
Uveal melanoma (UM) metastasis risk is linked to genetic changes like chromosome 3 loss and BAP1 mutations. These factors appear to act independently, suggesting a random, rather than sequential, development of metastatic potential in UM.
Area of Science:
- Ophthalmology
- Oncology
- Genetics
Background:
- Uveal melanoma (UM) metastasis risk is influenced by specific molecular alterations.
- The precise sequence of these genetic events in UM progression remains unclear.
Purpose of the Study:
- To investigate the interplay and sequence of key molecular lesions associated with UM metastasis.
- To analyze the combined effect of genetic factors on uveal melanoma patient outcomes.
Main Methods:
- Analysis of three independent uveal melanoma datasets (TCGA-UVM, GSE27831, GSE51880).
- Evaluation of mutations in SF3B1 and BAP1, and copy number alterations including chromosome 3 monosomy (M3), chromosome 8q gain (8q), and chromosome 6p gain (6p).
- Hierarchical clustering of gene expression data based on combinations of aggressivity factors.
Main Results:
- BAP1 mutations are consistently linked with chromosome 3 monosomy in high-risk UM.
- The genetic factors (6p gain, 8q gain, M3, SF3B1 mutation) generally occur independently.
- Gene expression patterns reveal distinct clusters associated with metastasis, particularly for combinations like 8q gain/M3 and BAP1 mutation/M3.
- Combined analysis of risk factors highlights additive effects on gene expression and outcome, not evident when considered individually.
Conclusions:
- The findings support a random risk model for UM metastasis, where genetic alterations act independently without a mandatory sequence.
- Understanding these independent risk factors and their combinations is crucial for predicting UM metastatic potential.
- Gene expression changes become more significant predictors of outcome when analyzed in the context of combined genetic alterations.
