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Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor pr...

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Autores principales: Hatipoğlu, Tevfik, Esmeray Sönmez, Esra, Hu, Xiaozhou, Yuan, Hongling, Danyeli, Ayça Erşen, Şeyhanlı, Ahmet, Önal-Süzek, Tuğba, Zhang, Weiwei, Akman, Burcu, Olgun, Aybüke, Özkal, Sermin, Alacacıoğlu, İnci, Özcan, Mehmet Ali, You, Hua, Küçük, Can
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252432/
https://www.ncbi.nlm.nih.gov/pubmed/35795062
http://dx.doi.org/10.3389/fonc.2022.870487
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author Hatipoğlu, Tevfik
Esmeray Sönmez, Esra
Hu, Xiaozhou
Yuan, Hongling
Danyeli, Ayça Erşen
Şeyhanlı, Ahmet
Önal-Süzek, Tuğba
Zhang, Weiwei
Akman, Burcu
Olgun, Aybüke
Özkal, Sermin
Alacacıoğlu, İnci
Özcan, Mehmet Ali
You, Hua
Küçük, Can
author_facet Hatipoğlu, Tevfik
Esmeray Sönmez, Esra
Hu, Xiaozhou
Yuan, Hongling
Danyeli, Ayça Erşen
Şeyhanlı, Ahmet
Önal-Süzek, Tuğba
Zhang, Weiwei
Akman, Burcu
Olgun, Aybüke
Özkal, Sermin
Alacacıoğlu, İnci
Özcan, Mehmet Ali
You, Hua
Küçük, Can
author_sort Hatipoğlu, Tevfik
collection PubMed
description Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.
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spelling pubmed-92524322022-07-05 Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis Hatipoğlu, Tevfik Esmeray Sönmez, Esra Hu, Xiaozhou Yuan, Hongling Danyeli, Ayça Erşen Şeyhanlı, Ahmet Önal-Süzek, Tuğba Zhang, Weiwei Akman, Burcu Olgun, Aybüke Özkal, Sermin Alacacıoğlu, İnci Özcan, Mehmet Ali You, Hua Küçük, Can Front Oncol Oncology Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature. Frontiers Media S.A. 2022-06-16 /pmc/articles/PMC9252432/ /pubmed/35795062 http://dx.doi.org/10.3389/fonc.2022.870487 Text en Copyright © 2022 Hatipoğlu, Esmeray Sönmez, Hu, Yuan, Danyeli, Şeyhanlı, Önal-Süzek, Zhang, Akman, Olgun, Özkal, Alacacıoğlu, Özcan, You and Küçük https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Hatipoğlu, Tevfik
Esmeray Sönmez, Esra
Hu, Xiaozhou
Yuan, Hongling
Danyeli, Ayça Erşen
Şeyhanlı, Ahmet
Önal-Süzek, Tuğba
Zhang, Weiwei
Akman, Burcu
Olgun, Aybüke
Özkal, Sermin
Alacacıoğlu, İnci
Özcan, Mehmet Ali
You, Hua
Küçük, Can
Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis
title Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis
title_full Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis
title_fullStr Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis
title_full_unstemmed Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis
title_short Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis
title_sort plasma concentrations and cancer-associated mutations in cell-free circulating dna of treatment-naive follicular lymphoma for improved non-invasive diagnosis and prognosis
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252432/
https://www.ncbi.nlm.nih.gov/pubmed/35795062
http://dx.doi.org/10.3389/fonc.2022.870487
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