Abstract
Growth differentiation factor 11 (GDF11), is a member of the transforming growth factor-beta (TGF-β) superfamily and bone morphogenetic protein (BMP) subfamily. In this study, we aimed to assess the expression profile of GDF11, its prognostic value in terms of OS, as well as the potential mechanisms leading to its dysregulation in uveal melanoma. A retrospective study was conducted using our primary data and genetic, clinicopathological and overall survival (OS) data from the Cancer Genome Atlas-Uveal Melanoma (TCGA-UVM). Results showed that GDF11 expression was significantly higher in tumor tissues compared with that in adjacent normal tissues. High GDF11 expression was associated with uveal melanoma in advanced stages (IV), epithelioid cell dominant subtype, as well as extrascleral extension. Univariate analysis showed that older age, epithelioid cell dominant, with extrascleral extension and increased GDF11 expression were associated with unfavorable OS. Multivariate analysis confirmed that GDF11 expression was an independent prognostic indicator of unfavorable OS (HR: 1.704, 95%CI: 1.143–2.540, p = 0.009), after adjustment of age, histological subtypes and extrascleral extension. Among the 80 cases of uveal melanoma, only 3 cases had low-level copy gain (+1) and 2 cases had heterozygous loss (-1). No somatic mutations, including SNPs and small INDELs were observed in GDF11 DNA. The methylation of these four CpG sites had weakly (cg22950598 and cg23689080), moderately (cg09890930), or strongly (cg05511733) negative correlation with GDF11 expression. In addition, the patients with high methylation of these four sites had significantly better OS compared to the group with low methylation. Based on these findings, we infer that methylation modulated GDF11 expression might be a valuable prognostic biomarker regarding OS in uveal melanoma.
Highlights
Uveal melanoma arises from the melanocytes residing within the uvea and is the most common primary intraocular cancer in adults [1]
By performing Quantitative real-time PCR (qPCR) assay, we examined Growth differentiation factor 11 (GDF11) expression in 19 cases of uveal melanoma tumor tissues and adjacent normal tissues
By grouping the tumor cases according to pathological stages, we found that stage in advanced stages (IV) tumors had the highest GDF11 expression (Fig 2A and 2B)
Summary
Uveal melanoma arises from the melanocytes residing within the uvea and is the most common primary intraocular cancer in adults [1]. The risk of metastasis and death varied significantly among patients with different stages of tumor. For stage III tumors, the metastasis and death rates at five years were 44% and 27%. GDF11 and overall-survival of uveal melanoma and death by one year [2]. Long-term survival is uncommon in patients with metastatic tumors, certain subsets of patients had long-term survival [3, 4]. The characteristics associated with long-term survival have not been fully understood
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