Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma

Desch AK, Hartung K, Botzen A, Brobeil A, Rummel M, Kurch L, Georgi T, Jox T, Bielack S, Burdach S, Classen CF, Claviez A, Debatin KM, Ebinger M, Eggert A, Faber J, Flotho C, Frühwald M, Graf N, Jorch N, Kontny U, Kramm C, Kulozik A, Kühr J, Sykora KW, Metzler M, Müller HL, Nathrath M, Nüßlein T, Paulussen M, Pekrun A, Reinhardt D, Reinhard H, Rössig C, Sauerbrey A, Schlegel PG, Schneider DT, Scheurlen W, Schweigerer L, Simon T, Suttorp M, Vorwerk P, Schmitz R, Kluge R, Mauz-Körholz C, Körholz D, Gattenlöhner S, Bräuninger A (2019)

Publication Type: Journal article

Publication year: 2019

Journal

DOI: 10.1038/s41375-019-0541-6

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.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Aachen (UKA) Germany (DE) Gemeinschaftsklinikum Mittelrhein Germany (DE) Justus-Liebig-Universität Gießen Germany (DE) Universität Leipzig Germany (DE) Otto-von-Guericke-Universität Magdeburg Germany (DE) Carl von Ossietzky Universität Oldenburg Germany (DE) Albert-Ludwigs-Universität Freiburg Germany (DE) Klinikum Dortmund Germany (DE) Universität Duisburg-Essen (UDE) Germany (DE) Universitätsklinikum Münster Germany (DE) Universitätsklinikum Würzburg Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) HELIOS Kliniken Germany (DE) Technische Universität München (TUM) Germany (DE) Klinikum Stuttgart Germany (DE) Universitätsklinikum Göttingen Germany (DE) Klinik Hallerwiese Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Technische Universität Dresden Germany (DE) Universität Witten/Herdecke Germany (DE) Universitätsklinikum Tübingen Germany (DE) Universitätsklinikum Augsburg Germany (DE) Universität zu Köln Germany (DE) Christian-Albrechts-Universität zu Kiel Germany (DE) Universität Rostock Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum des Saarlandes (UKS) Germany (DE) Klinikverbund Bremen (Gesundheit Nord) Germany (DE) Universitätsklinikum Ulm Germany (DE) Städtisches Klinikum Karlsruhe Germany (DE) Asklepios Kliniken Germany (DE) Klinikum Kassel GmbH Germany (DE) Johannes Gutenberg-Universität Mainz (JGU) Germany (DE)

How to cite

APA:

Desch, A.K., Hartung, K., Botzen, A., Brobeil, A., Rummel, M., Kurch, L.,... Bräuninger, A. (2019). Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma. Leukemia. https://dx.doi.org/10.1038/s41375-019-0541-6

MLA:

Desch, Ann Kathrin, et al. "Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma." Leukemia (2019).

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