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Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas

SIMPLE SUMMARY: Synovial sarcomas (SS) are rare soft tissue tumors of mesenchymal origin. Following resection of the primary tumor, about one third to half of the patients suffer from recurrence. Detection of local and distant recurrence during follow-up is commonly accomplished by imaging. There ar...

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Autores principales: Eisenhardt, Anja E., Brugger, Zacharias, Lausch, Ute, Kiefer, Jurij, Zeller, Johannes, Runkel, Alexander, Schmid, Adrian, Bronsert, Peter, Wehrle, Julius, Leithner, Andreas, Liegl-Atzwanger, Bernadette, Giunta, Riccardo E., Eisenhardt, Steffen U., Braig, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105697/
https://www.ncbi.nlm.nih.gov/pubmed/35565213
http://dx.doi.org/10.3390/cancers14092078
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author Eisenhardt, Anja E.
Brugger, Zacharias
Lausch, Ute
Kiefer, Jurij
Zeller, Johannes
Runkel, Alexander
Schmid, Adrian
Bronsert, Peter
Wehrle, Julius
Leithner, Andreas
Liegl-Atzwanger, Bernadette
Giunta, Riccardo E.
Eisenhardt, Steffen U.
Braig, David
author_facet Eisenhardt, Anja E.
Brugger, Zacharias
Lausch, Ute
Kiefer, Jurij
Zeller, Johannes
Runkel, Alexander
Schmid, Adrian
Bronsert, Peter
Wehrle, Julius
Leithner, Andreas
Liegl-Atzwanger, Bernadette
Giunta, Riccardo E.
Eisenhardt, Steffen U.
Braig, David
author_sort Eisenhardt, Anja E.
collection PubMed
description SIMPLE SUMMARY: Synovial sarcomas (SS) are rare soft tissue tumors of mesenchymal origin. Following resection of the primary tumor, about one third to half of the patients suffer from recurrence. Detection of local and distant recurrence during follow-up is commonly accomplished by imaging. There are no biomarkers available for routine diagnostics. We employ a highly sensitive targeted next-generation sequencing approach to monitor tumor dynamics by genotyping of circulating free DNA (cfDNA) in SS patients. cfDNA which harbors tumor-specific mutations (circulating tumor-DNA; ctDNA) correlated with the presence of viable tumor tissue. This enables timely and non-invasive detection of tumor recurrence and monitoring of treatment response independent of the anatomic location. ABSTRACT: Background: Synovial sarcoma (SS) is a malignant soft tissue tumor of mesenchymal origin that frequently occurs in young adults. Translocation of the SYT gene on chromosome 18 to the SSX genes on chromosome X leads to the formation of oncogenic fusion genes, which lead to initiation and proliferation of tumor cells. The detection and quantification of circulating tumor DNA (ctDNA) can serve as a non-invasive method for diagnostics of local or distant tumor recurrence, which could improve survival rates due to early detection. Methods: We developed a subtype-specific targeted next-generation sequencing (NGS) approach specifically targeting SS t(X;18)(p11;q11), which fuses SS18 (SYT) in chromosome 18 to SSX1 or SSX2 in chromosome x, and recurrent point mutations. In addition, patient-specific panels were designed from tumor exome sequencing. Both approaches were used to quantify ctDNA in patients’ plasma. Results: The subtype-specific assay allowed detection of somatic mutations from 25/25 tumors with a mean of 1.68 targetable mutations. The minimal limit of detection was determined at a variant allele frequency of 0.05%. Analysis of 29 plasma samples from 15 tumor patients identified breakpoint ctDNA in 6 patients (sensitivity: 40%, specificity 100%). The addition of more mutations further increased assay sensitivity. Quantification of ctDNA in plasma samples (n = 11) from one patient collected over 3 years, with a patient-specific panel based on tumor exome sequencing, correlated with the clinical course, response to treatment and tumor volume. Conclusions: Targeted NGS allows for highly sensitive tumor profiling and non-invasive detection of ctDNA in SS patients, enabling non-invasive monitoring of tumor dynamics.
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spelling pubmed-91056972022-05-14 Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas Eisenhardt, Anja E. Brugger, Zacharias Lausch, Ute Kiefer, Jurij Zeller, Johannes Runkel, Alexander Schmid, Adrian Bronsert, Peter Wehrle, Julius Leithner, Andreas Liegl-Atzwanger, Bernadette Giunta, Riccardo E. Eisenhardt, Steffen U. Braig, David Cancers (Basel) Article SIMPLE SUMMARY: Synovial sarcomas (SS) are rare soft tissue tumors of mesenchymal origin. Following resection of the primary tumor, about one third to half of the patients suffer from recurrence. Detection of local and distant recurrence during follow-up is commonly accomplished by imaging. There are no biomarkers available for routine diagnostics. We employ a highly sensitive targeted next-generation sequencing approach to monitor tumor dynamics by genotyping of circulating free DNA (cfDNA) in SS patients. cfDNA which harbors tumor-specific mutations (circulating tumor-DNA; ctDNA) correlated with the presence of viable tumor tissue. This enables timely and non-invasive detection of tumor recurrence and monitoring of treatment response independent of the anatomic location. ABSTRACT: Background: Synovial sarcoma (SS) is a malignant soft tissue tumor of mesenchymal origin that frequently occurs in young adults. Translocation of the SYT gene on chromosome 18 to the SSX genes on chromosome X leads to the formation of oncogenic fusion genes, which lead to initiation and proliferation of tumor cells. The detection and quantification of circulating tumor DNA (ctDNA) can serve as a non-invasive method for diagnostics of local or distant tumor recurrence, which could improve survival rates due to early detection. Methods: We developed a subtype-specific targeted next-generation sequencing (NGS) approach specifically targeting SS t(X;18)(p11;q11), which fuses SS18 (SYT) in chromosome 18 to SSX1 or SSX2 in chromosome x, and recurrent point mutations. In addition, patient-specific panels were designed from tumor exome sequencing. Both approaches were used to quantify ctDNA in patients’ plasma. Results: The subtype-specific assay allowed detection of somatic mutations from 25/25 tumors with a mean of 1.68 targetable mutations. The minimal limit of detection was determined at a variant allele frequency of 0.05%. Analysis of 29 plasma samples from 15 tumor patients identified breakpoint ctDNA in 6 patients (sensitivity: 40%, specificity 100%). The addition of more mutations further increased assay sensitivity. Quantification of ctDNA in plasma samples (n = 11) from one patient collected over 3 years, with a patient-specific panel based on tumor exome sequencing, correlated with the clinical course, response to treatment and tumor volume. Conclusions: Targeted NGS allows for highly sensitive tumor profiling and non-invasive detection of ctDNA in SS patients, enabling non-invasive monitoring of tumor dynamics. MDPI 2022-04-21 /pmc/articles/PMC9105697/ /pubmed/35565213 http://dx.doi.org/10.3390/cancers14092078 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Eisenhardt, Anja E.
Brugger, Zacharias
Lausch, Ute
Kiefer, Jurij
Zeller, Johannes
Runkel, Alexander
Schmid, Adrian
Bronsert, Peter
Wehrle, Julius
Leithner, Andreas
Liegl-Atzwanger, Bernadette
Giunta, Riccardo E.
Eisenhardt, Steffen U.
Braig, David
Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas
title Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas
title_full Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas
title_fullStr Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas
title_full_unstemmed Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas
title_short Genotyping of Circulating Free DNA Enables Monitoring of Tumor Dynamics in Synovial Sarcomas
title_sort genotyping of circulating free dna enables monitoring of tumor dynamics in synovial sarcomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105697/
https://www.ncbi.nlm.nih.gov/pubmed/35565213
http://dx.doi.org/10.3390/cancers14092078
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