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Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors
BACKGROUND: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003348/ https://www.ncbi.nlm.nih.gov/pubmed/32024476 http://dx.doi.org/10.1186/s12885-020-6597-x |
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author | Serrano, César Vivancos, Ana López-Pousa, Antonio Matito, Judit Mancuso, Francesco M. Valverde, Claudia Quiroga, Sergi Landolfi, Stefania Castro, Sandra Dopazo, Cristina Sebio, Ana Virgili, Anna C. Menso, María M. Martín-Broto, Javier Sansó, Miriam García-Valverde, Alfonso Rosell, Jordi Fletcher, Jonathan A. George, Suzanne Carles, Joan Arribas, Joaquín |
author_facet | Serrano, César Vivancos, Ana López-Pousa, Antonio Matito, Judit Mancuso, Francesco M. Valverde, Claudia Quiroga, Sergi Landolfi, Stefania Castro, Sandra Dopazo, Cristina Sebio, Ana Virgili, Anna C. Menso, María M. Martín-Broto, Javier Sansó, Miriam García-Valverde, Alfonso Rosell, Jordi Fletcher, Jonathan A. George, Suzanne Carles, Joan Arribas, Joaquín |
author_sort | Serrano, César |
collection | PubMed |
description | BACKGROUND: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. METHODS: We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). RESULTS: We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. CONCLUSIONS: ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics. |
format | Online Article Text |
id | pubmed-7003348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-70033482020-02-10 Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors Serrano, César Vivancos, Ana López-Pousa, Antonio Matito, Judit Mancuso, Francesco M. Valverde, Claudia Quiroga, Sergi Landolfi, Stefania Castro, Sandra Dopazo, Cristina Sebio, Ana Virgili, Anna C. Menso, María M. Martín-Broto, Javier Sansó, Miriam García-Valverde, Alfonso Rosell, Jordi Fletcher, Jonathan A. George, Suzanne Carles, Joan Arribas, Joaquín BMC Cancer Research Article BACKGROUND: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. METHODS: We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). RESULTS: We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. CONCLUSIONS: ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics. BioMed Central 2020-02-05 /pmc/articles/PMC7003348/ /pubmed/32024476 http://dx.doi.org/10.1186/s12885-020-6597-x Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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. |
spellingShingle | Research Article Serrano, César Vivancos, Ana López-Pousa, Antonio Matito, Judit Mancuso, Francesco M. Valverde, Claudia Quiroga, Sergi Landolfi, Stefania Castro, Sandra Dopazo, Cristina Sebio, Ana Virgili, Anna C. Menso, María M. Martín-Broto, Javier Sansó, Miriam García-Valverde, Alfonso Rosell, Jordi Fletcher, Jonathan A. George, Suzanne Carles, Joan Arribas, Joaquín Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors |
title | Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors |
title_full | Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors |
title_fullStr | Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors |
title_full_unstemmed | Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors |
title_short | Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors |
title_sort | clinical value of next generation sequencing of plasma cell-free dna in gastrointestinal stromal tumors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003348/ https://www.ncbi.nlm.nih.gov/pubmed/32024476 http://dx.doi.org/10.1186/s12885-020-6597-x |
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