Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma

Detalhes bibliográficos
Autor(a) principal: Bustamante, Prisca
Data de Publicação: 2021
Outros Autores: Tsering, Thupten, Coblentz, Jacqueline, Mastromonaco, Christina, Abdouh, Mohamed, Fonseca, Cristina, Proença, Rita Pinto, Blanchard, Nadya, Dugé, Claude Laure, Andujar, Rafaella Atherino Schmidt, Youhnovska, Emma, Burnier, Miguel N., Callejo, Sonia A., Burnier, Julia V.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/49535
Resumo: © The Author(s). 2021 Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
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spelling Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanomaAnimal modelBiomarkerChoroidal neviCirculating tumor DNAClinical specimensIn vitro studyLiquid biopsyMutated driver genesUveal melanoma© The Author(s). 2021 Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: 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.Springer NatureRepositório da Universidade de LisboaBustamante, PriscaTsering, ThuptenCoblentz, JacquelineMastromonaco, ChristinaAbdouh, MohamedFonseca, CristinaProença, Rita PintoBlanchard, NadyaDugé, Claude LaureAndujar, Rafaella Atherino SchmidtYouhnovska, EmmaBurnier, Miguel N.Callejo, Sonia A.Burnier, Julia V.2021-09-16T16:14:25Z20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/49535engJ Exp Clin Cancer Res. 2021 Jun 16;40(1):19610.1186/s13046-021-01984-w1756-9966info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:53:23Zoai:repositorio.ul.pt:10451/49535Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:01:09.600767Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
title Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
spellingShingle Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
Bustamante, Prisca
Animal model
Biomarker
Choroidal nevi
Circulating tumor DNA
Clinical specimens
In vitro study
Liquid biopsy
Mutated driver genes
Uveal melanoma
title_short Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
title_full Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
title_fullStr Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
title_full_unstemmed Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
title_sort Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma
author Bustamante, Prisca
author_facet Bustamante, Prisca
Tsering, Thupten
Coblentz, Jacqueline
Mastromonaco, Christina
Abdouh, Mohamed
Fonseca, Cristina
Proença, Rita Pinto
Blanchard, Nadya
Dugé, Claude Laure
Andujar, Rafaella Atherino Schmidt
Youhnovska, Emma
Burnier, Miguel N.
Callejo, Sonia A.
Burnier, Julia V.
author_role author
author2 Tsering, Thupten
Coblentz, Jacqueline
Mastromonaco, Christina
Abdouh, Mohamed
Fonseca, Cristina
Proença, Rita Pinto
Blanchard, Nadya
Dugé, Claude Laure
Andujar, Rafaella Atherino Schmidt
Youhnovska, Emma
Burnier, Miguel N.
Callejo, Sonia A.
Burnier, Julia V.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Bustamante, Prisca
Tsering, Thupten
Coblentz, Jacqueline
Mastromonaco, Christina
Abdouh, Mohamed
Fonseca, Cristina
Proença, Rita Pinto
Blanchard, Nadya
Dugé, Claude Laure
Andujar, Rafaella Atherino Schmidt
Youhnovska, Emma
Burnier, Miguel N.
Callejo, Sonia A.
Burnier, Julia V.
dc.subject.por.fl_str_mv Animal model
Biomarker
Choroidal nevi
Circulating tumor DNA
Clinical specimens
In vitro study
Liquid biopsy
Mutated driver genes
Uveal melanoma
topic Animal model
Biomarker
Choroidal nevi
Circulating tumor DNA
Clinical specimens
In vitro study
Liquid biopsy
Mutated driver genes
Uveal melanoma
description © The Author(s). 2021 Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
publishDate 2021
dc.date.none.fl_str_mv 2021-09-16T16:14:25Z
2021
2021-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/49535
url http://hdl.handle.net/10451/49535
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv J Exp Clin Cancer Res. 2021 Jun 16;40(1):196
10.1186/s13046-021-01984-w
1756-9966
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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