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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.870487/full |
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| author | Tevfik Hatipoğlu Tevfik Hatipoğlu Esra Esmeray Sönmez Esra Esmeray Sönmez Xiaozhou Hu Xiaozhou Hu Hongling Yuan Ayça Erşen Danyeli Ahmet Şeyhanlı Tuğba Önal-Süzek Weiwei Zhang Burcu Akman Burcu Akman Aybüke Olgun Sermin Özkal İnci Alacacıoğlu Mehmet Ali Özcan Hua You Can Küçük Can Küçük Can Küçük |
| author_facet | Tevfik Hatipoğlu Tevfik Hatipoğlu Esra Esmeray Sönmez Esra Esmeray Sönmez Xiaozhou Hu Xiaozhou Hu Hongling Yuan Ayça Erşen Danyeli Ahmet Şeyhanlı Tuğba Önal-Süzek Weiwei Zhang Burcu Akman Burcu Akman Aybüke Olgun Sermin Özkal İnci Alacacıoğlu Mehmet Ali Özcan Hua You Can Küçük Can Küçük Can Küçük |
| author_sort | Tevfik Hatipoğlu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T13:58:06Z |
| format | Article |
| id | doaj.art-a97d0c08e61d4d53a4a93208ea840177 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T13:58:06Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-a97d0c08e61d4d53a4a93208ea8401772022-12-22T03:30:19ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.870487870487Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and PrognosisTevfik Hatipoğlu0Tevfik Hatipoğlu1Esra Esmeray Sönmez2Esra Esmeray Sönmez3Xiaozhou Hu4Xiaozhou Hu5Hongling Yuan6Ayça Erşen Danyeli7Ahmet Şeyhanlı8Tuğba Önal-Süzek9Weiwei Zhang10Burcu Akman11Burcu Akman12Aybüke Olgun13Sermin Özkal14İnci Alacacıoğlu15Mehmet Ali Özcan16Hua You17Can Küçük18Can Küçük19Can Küçük20İzmir Biomedicine and Genome Center, İzmir, Turkeyİzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkeyİzmir Biomedicine and Genome Center, İzmir, Turkeyİzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkeyİzmir Biomedicine and Genome Center, İzmir, Turkeyİzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, Turkeyİzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, TurkeyDepartment of Pathology, Faculty of Medicine, Dokuz Eylül University, İzmir, TurkeyDepartment of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, TurkeyDepartment of Bioinformatics, Graduate School of Natural and Applied Sciences, Muğla Sıtkı Koçman University, Muğla, TurkeyDepartment of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United Statesİzmir Biomedicine and Genome Center, İzmir, Turkeyİzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, TurkeyDepartment of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, TurkeyDepartment of Pathology, Faculty of Medicine, Dokuz Eylül University, İzmir, TurkeyDepartment of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, TurkeyDepartment of Hematology, Faculty of Medicine, Dokuz Eylül University, İzmir, TurkeyDepartment of Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Chinaİzmir Biomedicine and Genome Center, İzmir, Turkeyİzmir International Biomedicine and Genome Institute, Dokuz Eylül University, İzmir, TurkeyDepartment of Medical Biology, Faculty of Medicine, Dokuz Eylül University, İzmir, TurkeyFollicular 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.https://www.frontiersin.org/articles/10.3389/fonc.2022.870487/fullfollicular lymphomaliquid biopsycfDNA genotypingtargeted ultra-deep sequencingnon-invasive diagnosisprognosis |
| spellingShingle | Tevfik Hatipoğlu Tevfik Hatipoğlu Esra Esmeray Sönmez Esra Esmeray Sönmez Xiaozhou Hu Xiaozhou Hu Hongling Yuan Ayça Erşen Danyeli Ahmet Şeyhanlı Tuğba Önal-Süzek Weiwei Zhang Burcu Akman Burcu Akman Aybüke Olgun Sermin Özkal İnci Alacacıoğlu Mehmet Ali Özcan Hua You Can Küçük Can Küçük Can Küçük Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis Frontiers in Oncology follicular lymphoma liquid biopsy cfDNA genotyping targeted ultra-deep sequencing non-invasive diagnosis 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 | follicular lymphoma liquid biopsy cfDNA genotyping targeted ultra-deep sequencing non-invasive diagnosis prognosis |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.870487/full |
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