Abstract
Despite outstanding advances in diagnosis and the treatment of primary uveal melanoma (UM), nearly 50% of UM patients develop metastases via hematogenous dissemination, driven by the epithelial-mesenchymal transition (EMT). Despite the failure in UM to date, a liquid biopsy may offer a feasible non-invasive approach for monitoring metastatic disease progression and addressing protracted dormancy. To detect circulating tumor cells (CTCs) in UM patients, we evaluated the mRNA expression of EMT-associated transcription factors in CD45-depleted blood fraction, using qRT-PCR. ddPCR was employed to assess UM-specific GNA11, GNAQ, PLCβ4, and CYSLTR2 mutations in plasma DNA. Moreover, microarray analysis was performed on total RNA isolated from tumor tissues to estimate the prognostic value of EMT-associated gene expression. In total, 42 primary UM and 11 metastatic patients were enrolled. All CD45-depleted samples were negative for CTC when compared to the peripheral blood fraction of 60 healthy controls. Tumor-specific mutations were detected in the plasma of 21.4% patients, merely, in 9.4% of primary UM, while 54.5% in metastatic patients. Unsupervised hierarchical clustering of differentially expressed EMT genes showed significant differences between monosomy 3 and disomy 3 tumors. Newly identified genes can serve as non-invasive prognostic biomarkers that can support therapeutic decisions.
Highlights
Uveal melanoma (UM), comprising approximately 83% of ocular and 3% of all melanomas, is the most frequent intraocular tumor in adults [1]
* one metastatic patient was enrolled 31 months after enucleation, tumor tissue was not available; $ only tumor tissues which were not treated by stereotactic radiosurgery in the past were analyzed; Abbreviations: TNM classification, T, size of the tumor; N, involvement on lymph nodes; M, presence of distant metastasis; MLPA, Multiplex Ligation-Dependent Probe Amplification; C69.3, malignant neoplasm of choroid; C69.4, malignant neoplasm of the ciliary body
As chromosome 3 monosomy strongly correlates with metastatic death, while chromosome 8 gains occur later in UM tumorigenesis, we focus on monosomy 3 (M3) only
Summary
Uveal melanoma (UM), comprising approximately 83% of ocular and 3% of all melanomas, is the most frequent intraocular tumor in adults [1]. The UM tumors derive from the uveal layer of the eye; the choroid is the most frequent location (82%), with remaining cases originating from the ciliary body (15%) and iris (3%) [3]. Most UM patients survive less than 12 months after metastases diagnosis by virtue of no efficient therapies for metastatic UM [4]. Pathological, molecular, and cytogenetic markers assessed in tumors can predict the risk of metastases and survival. Clinical and histopathological factors associated with poor prognosis include extra-vascular matrix pattern, epithelioid melanoma cytomorphology, high mitotic rate, and inflammatory infiltration, their sensitivity and specificity are limited [5]
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