Abstract
Simple SummaryUveal melanoma (UM) is a heterogeneous disease driven by accumulative alterations at multi-omics levels including genomics, epigenomics and transcriptomics. It is of great clinical interest to identify UM molecular subtypes and subtype-specific biomarkers that could be used for prognosis and targeted therapy. Integrative clustering (iCluster) analysis is a new approach designed to identify cancer integrative subtypes (iSubtypes) and multi-omics signatures that drive molecular classification of cancer. In this study, we performed an iCluster analysis of UM multi-omics data and identified four UM iSubtypes, which formed two major iSubtypes (denoted by M3 and D3) with distinct multi-omics landscapes. We showed that the integrative molecular classification of UM was determined by concordant alterations at multi-omics levels including DNA copy number, DNA methylation, gene expression and somatic mutation. We further derived a gene panel that can be used to classify UM into high- or low-risk groups for metastasis.By iCluster analysis, we found that the integrative molecular classification of the UM was primarily driven by DNA copy number variation on chromosomes 3, 6 and 8, differential methylation and expression of genes involved in the immune system, cell morphogenesis, movement and migration, and differential mutation of genes including GNA11, BAP1, EIF1AX, SF3B1 and GNAQ. Integrative analysis revealed that pathways including IL6/JAK/STAT3 signaling, angiogenesis, allograft rejection, inflammatory response and interferon gamma response were hypomethylated and up-regulated in the M3 iSubtype, which was associated with a worse overall survival, compared to the D3 iSubtype. Using two independent gene expression datasets, we demonstrated that the subtype-driving genes had an excellent prognostic power in classifying UM into high- or low-risk groups for metastasis. Integrative analysis of UM multi-omics data provided a comprehensive view of UM biology for understanding the underlying mechanism leading to UM metastasis. The concordant molecular alterations at multi-omics levels revealed by our integrative analysis could be used for patient stratification towards personalized management and surveillance.
Highlights
Uveal melanoma (UM), originating from melanocytes within the uveal tract of the eye, is a relatively rare cancer, with a mean age-adjusted incidence of 5.1 cases per million per year in the United States [1]
The iCluster analysis revealed that, in general, M3 coexisted with 8q gain, and D3 coexisted with 6p gain, while M3/8q gain and 6p gain appeared to be mutually exclusive (Figure 1B, copy number)
Through iCluster analysis, we showed that the integrative clustering of UM samples was primarily driven by the alterations in chromosomes 3, 6 and 8, as well as differential methylation, gene expression and mutation patterns, which were not revealed by individual clustering analysis as reported by Robertson et al [12]
Summary
Uveal melanoma (UM), originating from melanocytes within the uveal tract of the eye, is a relatively rare cancer, with a mean age-adjusted incidence of 5.1 cases per million per year in the United States [1]. It is the most common cancer of the eye and the second most common form of melanoma after cutaneous melanoma (CM). Genetic features including loss of a copy of chromosome 3 (monosomy 3), mutations in BAP1 (BRCA-associated protein 1) and gain of chromosome 8q were often found to coexist in UM and were associated with high risk of metastasis [4,5,6,7]. In a retrospective study of 661 patients diagnosed with metastatic UM over three decades (1982–2011), the median survival time was less than a half year; the one-year survival rate was about 21%, and the three-year survival rate was less than 5% [11]
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