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Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up

PURPOSE: As noninvasive biomarkers are an important unmet need for neuroendocrine neoplasms (NEN), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in patients with NEN. EXPERIMENTAL DESIGN: Longitudinal plasma samples were collected fr...

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Autores principales: Boons, Gitta, Vandamme, Timon, Mariën, Laura, Lybaert, Willem, Roeyen, Geert, Rondou, Tim, Papadimitriou, Konstantinos, Janssens, Katrien, Op de Beeck, Bart, Simoens, Marc, Demey, Wim, Dero, Isabel, Van Camp, Guy, Peeters, Marc, Op de Beeck, Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401546/
https://www.ncbi.nlm.nih.gov/pubmed/34759042
http://dx.doi.org/10.1158/1078-0432.CCR-21-2291
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author Boons, Gitta
Vandamme, Timon
Mariën, Laura
Lybaert, Willem
Roeyen, Geert
Rondou, Tim
Papadimitriou, Konstantinos
Janssens, Katrien
Op de Beeck, Bart
Simoens, Marc
Demey, Wim
Dero, Isabel
Van Camp, Guy
Peeters, Marc
Op de Beeck, Ken
author_facet Boons, Gitta
Vandamme, Timon
Mariën, Laura
Lybaert, Willem
Roeyen, Geert
Rondou, Tim
Papadimitriou, Konstantinos
Janssens, Katrien
Op de Beeck, Bart
Simoens, Marc
Demey, Wim
Dero, Isabel
Van Camp, Guy
Peeters, Marc
Op de Beeck, Ken
author_sort Boons, Gitta
collection PubMed
description PURPOSE: As noninvasive biomarkers are an important unmet need for neuroendocrine neoplasms (NEN), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in patients with NEN. EXPERIMENTAL DESIGN: Longitudinal plasma samples were collected from patients with well-differentiated, metastatic gastroenteropancreatic and lung NEN. cfDNA was subjected to shallow whole-genome sequencing to detect genome-wide copy-number alterations (CNA) and estimate circulating tumor DNA (ctDNA) fraction, and correlated to clinicopathologic and survival data. To differentiate pancreatic NENs (PNEN) from pancreatic adenocarcinomas (PAAD) using liquid biopsies, a classification model was trained using tissue-based CNAs and validated in cfDNA. RESULTS: One hundred and ninety-five cfDNA samples from 43 patients with NEN were compared with healthy control cfDNA (N = 100). Plasma samples from patients with PNEN (N = 21) were used for comparison with publicly available PNEN tissue (N = 98), PAAD tissue (N = 109), and PAAD cfDNA (N = 96). Thirty percent of the NEN cfDNA samples contained ctDNA and 44% of the patients had at least one ctDNA-positive (ctDNA(+)) sample. CNAs detected in cfDNA were highly specific for NENs and the classification model could distinguish PAAD and PNEN cfDNA samples with a sensitivity, specificity, and AUC of 62%, 86%, and 79%, respectively. ctDNA-positivity was associated with higher World Health Organization (WHO) grade, primary tumor location, and higher chromogranin A and neuron-specific enolase values. Overall survival was significantly worse for ctDNA(+) patients and increased ctDNA fractions were associated with poorer progression-free survival. CONCLUSIONS: Sequential genome-wide profiling of plasma cfDNA is a novel, noninvasive biomarker with high specificity for diagnosis, prognosis, and follow-up in metastatic NENs.
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spelling pubmed-94015462023-01-05 Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up Boons, Gitta Vandamme, Timon Mariën, Laura Lybaert, Willem Roeyen, Geert Rondou, Tim Papadimitriou, Konstantinos Janssens, Katrien Op de Beeck, Bart Simoens, Marc Demey, Wim Dero, Isabel Van Camp, Guy Peeters, Marc Op de Beeck, Ken Clin Cancer Res Precision Medicine and Imaging PURPOSE: As noninvasive biomarkers are an important unmet need for neuroendocrine neoplasms (NEN), biomarker potential of genome-wide molecular profiling of plasma cell-free DNA (cfDNA) was prospectively studied in patients with NEN. EXPERIMENTAL DESIGN: Longitudinal plasma samples were collected from patients with well-differentiated, metastatic gastroenteropancreatic and lung NEN. cfDNA was subjected to shallow whole-genome sequencing to detect genome-wide copy-number alterations (CNA) and estimate circulating tumor DNA (ctDNA) fraction, and correlated to clinicopathologic and survival data. To differentiate pancreatic NENs (PNEN) from pancreatic adenocarcinomas (PAAD) using liquid biopsies, a classification model was trained using tissue-based CNAs and validated in cfDNA. RESULTS: One hundred and ninety-five cfDNA samples from 43 patients with NEN were compared with healthy control cfDNA (N = 100). Plasma samples from patients with PNEN (N = 21) were used for comparison with publicly available PNEN tissue (N = 98), PAAD tissue (N = 109), and PAAD cfDNA (N = 96). Thirty percent of the NEN cfDNA samples contained ctDNA and 44% of the patients had at least one ctDNA-positive (ctDNA(+)) sample. CNAs detected in cfDNA were highly specific for NENs and the classification model could distinguish PAAD and PNEN cfDNA samples with a sensitivity, specificity, and AUC of 62%, 86%, and 79%, respectively. ctDNA-positivity was associated with higher World Health Organization (WHO) grade, primary tumor location, and higher chromogranin A and neuron-specific enolase values. Overall survival was significantly worse for ctDNA(+) patients and increased ctDNA fractions were associated with poorer progression-free survival. CONCLUSIONS: Sequential genome-wide profiling of plasma cfDNA is a novel, noninvasive biomarker with high specificity for diagnosis, prognosis, and follow-up in metastatic NENs. American Association for Cancer Research 2022-01-15 2021-11-10 /pmc/articles/PMC9401546/ /pubmed/34759042 http://dx.doi.org/10.1158/1078-0432.CCR-21-2291 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Precision Medicine and Imaging
Boons, Gitta
Vandamme, Timon
Mariën, Laura
Lybaert, Willem
Roeyen, Geert
Rondou, Tim
Papadimitriou, Konstantinos
Janssens, Katrien
Op de Beeck, Bart
Simoens, Marc
Demey, Wim
Dero, Isabel
Van Camp, Guy
Peeters, Marc
Op de Beeck, Ken
Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up
title Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up
title_full Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up
title_fullStr Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up
title_full_unstemmed Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up
title_short Longitudinal Copy-Number Alteration Analysis in Plasma Cell-Free DNA of Neuroendocrine Neoplasms is a Novel Specific Biomarker for Diagnosis, Prognosis, and Follow-up
title_sort longitudinal copy-number alteration analysis in plasma cell-free dna of neuroendocrine neoplasms is a novel specific biomarker for diagnosis, prognosis, and follow-up
topic Precision Medicine and Imaging
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9401546/
https://www.ncbi.nlm.nih.gov/pubmed/34759042
http://dx.doi.org/10.1158/1078-0432.CCR-21-2291
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