Desch, Ann-Kathrin, Hartung, Kristin, Botzen, Ante, Brobeil, Alexander, Rummel, Mathias, Kurch, Lars, Georgi, Thomas, Jox, Theresa, Bielack, Stefan, Burdach, Stefan, Classen, Carl Friedrich, Claviez, Alexander, Debatin, Klaus-Michael ORCID: 0000-0002-8397-1886, Ebinger, Martin ORCID: 0000-0002-4229-8058, Eggert, Angelika ORCID: 0000-0003-3476-8184, Faber, Joerg, Flotho, Christian, Fruehwald, Michael, Graf, Norbert ORCID: 0000-0002-2248-323X, Jorch, Norbert, Kontny, Udo, Kramm, Christof, Kulozik, Andreas, Kuehr, Joachim, Sykora, Karl-Walter, Metzler, Markus, Mueller, Hermann L., Nathrath, Michaela, Nuesslein, Thomas, Paulussen, Michael, Pekrun, Arnulf, Reinhardt, Dirk, Reinhard, Harald, Roessig, Claudia, Sauerbrey, Axel, Schlegel, Paul-Gerhardt, Schneider, Dominik T., Scheurlen, Wolfram, Schweigerer, Lothar, Simon, Thorsten, Suttorp, Meinolf, Vorwerk, Peter, Schmitz, Roland, Kluge, Regine, Mauz-Koerholz, Christine, Koerholz, Dieter, Gattenloehner, Stefan and Braeuninger, Andreas (2020). Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma. Leukemia, 34 (1). S. 151 - 167. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5551

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Abstract

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET < 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET > 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Desch, Ann-KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartung, KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Botzen, AnteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brobeil, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rummel, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurch, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Georgi, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jox, TheresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bielack, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burdach, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Classen, Carl FriedrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claviez, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Debatin, Klaus-MichaelUNSPECIFIEDorcid.org/0000-0002-8397-1886UNSPECIFIED
Ebinger, MartinUNSPECIFIEDorcid.org/0000-0002-4229-8058UNSPECIFIED
Eggert, AngelikaUNSPECIFIEDorcid.org/0000-0003-3476-8184UNSPECIFIED
Faber, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flotho, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fruehwald, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graf, NorbertUNSPECIFIEDorcid.org/0000-0002-2248-323XUNSPECIFIED
Jorch, NorbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kontny, UdoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kramm, ChristofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kulozik, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuehr, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sykora, Karl-WalterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Metzler, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Hermann L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nathrath, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuesslein, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paulussen, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pekrun, ArnulfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhard, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roessig, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sauerbrey, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlegel, Paul-GerhardtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, Dominik T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheurlen, WolframUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweigerer, LotharUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simon, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suttorp, MeinolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vorwerk, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitz, RolandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kluge, RegineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mauz-Koerholz, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koerholz, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gattenloehner, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braeuninger, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-351104
DOI: 10.1038/s41375-019-0541-6
Journal or Publication Title: Leukemia
Volume: 34
Number: 1
Page Range: S. 151 - 167
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5551
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
B-CELL LYMPHOMA; MARGINAL ZONE LYMPHOMA; REED-STERNBERG CELLS; EPSTEIN-BARR-VIRUS; SOMATIC MUTATIONS; GENETIC-HETEROGENEITY; MULTIPLE-MYELOMA; CLONAL EVOLUTION; CODING GENOME; RECURRENTMultiple languages
Oncology; HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/35110

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