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Circulating Tumor DNA Tracking Through Driver Mutations as a Liquid Biopsy-Based Biomarker for Uveal Melanoma

2021Journal article Open access
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dc.contributor.authorBustamante, P
dc.contributor.authorTsering, T
dc.contributor.authorCoblentz, J
dc.contributor.authorMastromonaco, C
dc.contributor.authorAbdouh, M
dc.contributor.authorFonseca, C
dc.contributor.authorProença, RP
dc.contributor.authorBlanchard, N
dc.contributor.authorDugé, CL
dc.contributor.authorAndujar, RAS
dc.contributor.authorYouhnovska, E
dc.contributor.authorBurnier, MN
dc.contributor.authorCallejo, SA
dc.contributor.authorBurnier, JV
dc.date.accessioned2023-01-26T16:14:40Z
dc.date.available2023-01-26T16:14:40Z
dc.date.issued2021
dc.description.abstractBackground: Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite good primary tumor control, up to 50% of patients develop metastasis, which is lethal. UM often presents asymptomatically and is usually diagnosed by clinical examination and imaging, making it one of the few cancer types diagnosed without a biopsy. Hence, alternative diagnostic tools are needed. Circulating tumor DNA (ctDNA) has shown potential as a liquid biopsy target for cancer screening and monitoring. The aim of this study was to evaluate the feasibility and clinical utility of ctDNA detection in UM using specific UM gene mutations. Methods: We used the highly sensitive digital droplet PCR (ddPCR) assay to quantify UM driver mutations (GNAQ, GNA11, PLCβ4 and CYSTLR2) in cell-free DNA (cfDNA). cfDNA was analyzed in six well established human UM cell lines with known mutational status. cfDNA was analyzed in the blood and aqueous humor of an UM rabbit model and in the blood of patients. Rabbits were inoculated with human UM cells into the suprachoroidal space, and mutated ctDNA was quantified from longitudinal peripheral blood and aqueous humor draws. Blood clinical specimens were obtained from primary UM patients (n = 14), patients presenting with choroidal nevi (n = 16) and healthy individuals (n = 15). Results: The in vitro model validated the specificity and accuracy of ddPCR to detect mutated cfDNA from UM cell supernatant. In the rabbit model, plasma and aqueous humor levels of ctDNA correlated with tumor growth. Notably, the detection of ctDNA preceded clinical detection of the intraocular tumor. In human specimens, while we did not detect any trace of ctDNA in healthy controls, we detected ctDNA in all UM patients. We observed that UM patients had significantly higher levels of ctDNA than patients with nevi, with a strong correlation between ctDNA levels and malignancy. Noteworthy, in patients with nevi, the levels of ctDNA highly correlated with the presence of clinical risk factors. Conclusions: We report, for the first time, compelling evidence from in vitro assays, and in vivo animal model and clinical specimens for the potential of mutated ctDNA as a biomarker of UM progression. These findings pave the way towards the implementation of a liquid biopsy to detect and monitor UM tumors.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Exp Clin Cancer Res . 2021 Jun 16;40(1):196pt_PT
dc.identifier.doi10.1186/s13046-021-01984-wpt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/4362
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherBiomed Centralpt_PT
dc.subjectAnimal modelpt_PT
dc.subjectBiomarkerpt_PT
dc.subjectChoroidal nevipt_PT
dc.subjectCirculating tumor DNApt_PT
dc.subjectClinical specimenspt_PT
dc.subjectIn vitro studypt_PT
dc.subjectLiquid biopsypt_PT
dc.subjectMutated driver genespt_PT
dc.subjectUveal melanomapt_PT
dc.subjectHSAC OFTpt_PT
dc.titleCirculating Tumor DNA Tracking Through Driver Mutations as a Liquid Biopsy-Based Biomarker for Uveal Melanomapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue1pt_PT
oaire.citation.startPage196pt_PT
oaire.citation.titleJournal of Experimental & Clinical Cancer Researchpt_PT
oaire.citation.volume40pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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