Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA
Abstract Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13045-023-01500-x |
| _version_ | 1797451773671112704 |
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| author | Nick Veltmaat Yujie Zhong Filipe Montes de Jesus Geok Wee Tan Johanna A. A. Bult Martijn M. Terpstra Pim G. N. J. Mutsaers Wendy B. C. Stevens Rogier Mous Joost S. P. Vermaat Martine E. D. Chamuleau Walter Noordzij Erik A. M. Verschuuren Klaas Kok Joost L. Kluiver Arjan Diepstra Wouter J. Plattel Anke van den Berg Marcel Nijland |
| author_facet | Nick Veltmaat Yujie Zhong Filipe Montes de Jesus Geok Wee Tan Johanna A. A. Bult Martijn M. Terpstra Pim G. N. J. Mutsaers Wendy B. C. Stevens Rogier Mous Joost S. P. Vermaat Martine E. D. Chamuleau Walter Noordzij Erik A. M. Verschuuren Klaas Kok Joost L. Kluiver Arjan Diepstra Wouter J. Plattel Anke van den Berg Marcel Nijland |
| author_sort | Nick Veltmaat |
| collection | DOAJ |
| description | Abstract Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring. |
| first_indexed | 2024-03-09T14:59:15Z |
| format | Article |
| id | doaj.art-9e6d8c46862e487885e9719b47a06740 |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-03-09T14:59:15Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-9e6d8c46862e487885e9719b47a067402023-11-26T14:01:39ZengBMCJournal of Hematology & Oncology1756-87222023-09-011611510.1186/s13045-023-01500-xGenomic profiling of post-transplant lymphoproliferative disorders using cell-free DNANick Veltmaat0Yujie Zhong1Filipe Montes de Jesus2Geok Wee Tan3Johanna A. A. Bult4Martijn M. Terpstra5Pim G. N. J. Mutsaers6Wendy B. C. Stevens7Rogier Mous8Joost S. P. Vermaat9Martine E. D. Chamuleau10Walter Noordzij11Erik A. M. Verschuuren12Klaas Kok13Joost L. Kluiver14Arjan Diepstra15Wouter J. Plattel16Anke van den Berg17Marcel Nijland18Department of Hematology, University Medical Centre Groningen, University of GroningenDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of GroningenMedical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, University of GroningenDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of GroningenDepartment of Hematology, University Medical Centre Groningen, University of GroningenDepartment of Genetics, University Medical Centre Groningen, University of GroningenDepartment of Hematology, Erasmus Medical Centre RotterdamDepartment of Hematology, Radboud University Medical Center NijmegenDepartment of Hematology, University Medical Center UtrechtDepartment of Hematology, Leiden University Medical CenterDepartment of Hematology, Amsterdam University Medical CenterMedical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, University of GroningenDepartment of Pulmonology, University Medical Centre Groningen, University of GroningenDepartment of Genetics, University Medical Centre Groningen, University of GroningenDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of GroningenDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of GroningenDepartment of Hematology, University Medical Centre Groningen, University of GroningenDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of GroningenDepartment of Hematology, University Medical Centre Groningen, University of GroningenAbstract Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring.https://doi.org/10.1186/s13045-023-01500-xPost-transplant lymphoproliferative disorderCell-free DNAGenomic profilingLiquid biopsyEpstein–Barr virusCopy number variation |
| spellingShingle | Nick Veltmaat Yujie Zhong Filipe Montes de Jesus Geok Wee Tan Johanna A. A. Bult Martijn M. Terpstra Pim G. N. J. Mutsaers Wendy B. C. Stevens Rogier Mous Joost S. P. Vermaat Martine E. D. Chamuleau Walter Noordzij Erik A. M. Verschuuren Klaas Kok Joost L. Kluiver Arjan Diepstra Wouter J. Plattel Anke van den Berg Marcel Nijland Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA Journal of Hematology & Oncology Post-transplant lymphoproliferative disorder Cell-free DNA Genomic profiling Liquid biopsy Epstein–Barr virus Copy number variation |
| title | Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA |
| title_full | Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA |
| title_fullStr | Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA |
| title_full_unstemmed | Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA |
| title_short | Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA |
| title_sort | genomic profiling of post transplant lymphoproliferative disorders using cell free dna |
| topic | Post-transplant lymphoproliferative disorder Cell-free DNA Genomic profiling Liquid biopsy Epstein–Barr virus Copy number variation |
| url | https://doi.org/10.1186/s13045-023-01500-x |
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