Abstract
PurposeTo evaluate the feasibility of using circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) for the management of uveal melanoma (UM).Patients and MethodsLow-coverage whole-genome sequencing was used to determine somatic chromosomal copy number alterations (SCNAs) in primary UM tumors, ctDNA, and whole-genome amplified CTCs. CTCs were immunocaptured using an antimelanoma-associated chondroitin sulfate antibody conjugated to magnetic beads and immunostained for melanoma antigen recognised by T cells 1 (MART1)/glycoprotein 100 (gp100)/S100 calcium-binding protein β (S100β). ctDNA was quantified using droplet digital polymerase chain reaction assay for mutations in the GNAQ, GNA11, PLCβ4, and CYSLTR2 genes.ResultsSCNA analysis of CTCs and ctDNA isolated from a patient with metastatic UM showed good concordance with the enucleated primary tumor. In a cohort of 30 patients with primary UM, CTCs were detected in 58% of patients (one to 37 CTCs per 8 mL of blood), whereas only 26% of patients had detectable ctDNA (1.6 to 29 copies/mL). The presence of CTCs or ctDNA was not associated with tumor size or other prognostic markers. However, the frequent detection of CTCs in patients with early-stage UM supports a model in which CTCs can be used to derive tumor-specific SCNA relevant for prognosis. Monitoring of ctDNA after treatment of the primary tumor allowed detection of metastatic disease earlier than 18F-labeled fluorodeoxyglucose positron emission tomography in two patients.ConclusionThe presence of CTCs in localized UM can be used to ascertain prognostic SCNA, whereas ctDNA can be used to monitor patients for early signs of metastatic disease. This study paves the way for the analysis of CTCs and ctDNA as a liquid biopsy that will assist with treatment decisions in patients with UM.
Highlights
Uveal melanoma (UM) is the most common intraocular malignancy.[1]
circulating tumor cells (CTCs) were isolated from peripheral venous blood of a patient with metastatic UM
A single peripheral blood mononuclear cell (PBMC) subjected to whole-genome amplified (WGA) was used as negative control
Summary
Uveal melanoma (UM) is the most common intraocular malignancy.[1] Despite successful control of the primary tumor within the eye, metastatic disease develops in up to 50% of patients, predominantly in the liver. There are limited therapeutic options for metastatic UM, and as a result there is a high mortality rate.[2] Extensive analysis of primary UMs has defined molecular features of the tumor cells that predict, with a high degree of accuracy, a patient’s risk for development of metastases. Biomarkers of poor prognosis include histopathological features of the tumor; somatic copy number alterations (SCNAs), such as loss of chromosome. 3, 6q, and 8q3,4; BAP1 mutations[5,6]; and the differential expression of marker genes that include well-characterized cancer-associated factors.[7,8] Other features, such as gain in 6p and mutations in EIF1AX and SF3B1, are associated with better prognosis.[4,6]
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