Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma

被引：68

作者：

Desch, Ann-Kathrin ^{[1
]}

Hartung, Kristin ^{[1
]}

Botzen, Ante ^{[2
]}

Brobeil, Alexander ^{[1
]}

Rummel, Mathias ^{[3
]}

Kurch, Lars ^{[4
]}

Georgi, Thomas ^{[4
]}

Jox, Theresa ^{[2
]}

Bielack, Stefan ^{[5
]}

Burdach, Stefan ^{[6
,7
,8
]}

Classen, Carl Friedrich ^{[9
]}

Claviez, Alexander ^{[10
]}

Debatin, Klaus-Michael ^{[11
]}

Ebinger, Martin ^{[12
]}

Eggert, Angelika ^{[13
]}

Faber, Joerg ^{[14
]}

Flotho, Christian ^{[15
]}

Fruehwald, Michael ^{[16
]}

Graf, Norbert ^{[17
]}

Jorch, Norbert ^{[18
]}

Kontny, Udo ^{[19
]}

Kramm, Christof ^{[20
]}

Kulozik, Andreas ^{[21
,22
]}

Kuehr, Joachim ^{[23
]}

Sykora, Karl-Walter ^{[24
]}

Metzler, Markus ^{[25
]}

Mueller, Hermann L. ^{[26
]}

Nathrath, Michaela ^{[27
]}

Nuesslein, Thomas ^{[28
]}

Paulussen, Michael ^{[29
]}

Pekrun, Arnulf ^{[30
]}

Reinhardt, Dirk ^{[31
]}

Reinhard, Harald ^{[32
]}

Roessig, Claudia ^{[33
]}

Sauerbrey, Axel ^{[34
]}

Schlegel, Paul-Gerhardt ^{[35
]}

Schneider, Dominik T. ^{[36
]}

Scheurlen, Wolfram ^{[37
]}

Schweigerer, Lothar ^{[38
]}

Simon, Thorsten ^{[39
]}

Suttorp, Meinolf ^{[40
]}

Vorwerk, Peter ^{[41
]}

Schmitz, Roland ^{[1
]}

Kluge, Regine ^{[4
]}

Mauz-Koerholz, Christine ^{[2
,42
]}

Koerholz, Dieter ^{[2
]}

Gattenloehner, Stefan ^{[1
]}

Braeuninger, Andreas ^{[1
]}

机构：

[1] Justus Liebig Univ, Inst Pathol, Giessen, Germany

[2] Justus Liebig Univ, Dept Pediat Oncol & Hematol, Giessen, Germany

[3] Justus Liebig Univ, Dept Internal Med, Hematol, Giessen, Germany

[4] Univ Leipzig, Clin Nucl Med, Leipzig, Germany

[5] Olga Hosp, Klinikum Stuttgart, Stuttgart Canc Ctr, Pediat 5,Oncol,Hematol,Immunol, Stuttgart, Germany

[6] Tech Univ Munich, Clin Children Munchen Schwabing, Munich, Germany

[7] CCC Munchen Comprehens Canc Ctr, Munich, Germany

[8] DKTK German Canc Consortium Munich, Munich, Germany

[9] Univ Rostock, Clin Children & Adolescents, Rostock, Germany

[10] Univ Schleswig Holstein, Clin Children & Adolescent Med, Kiel, Germany

[11] Ulm Univ, Med Ctr, Dept Pediat & Adolescent Med, Ulm, Germany

[12] Eberhard Karls Univ Tubingen, Univ Clin Children & Adolescents, Tubingen, Germany

[13] Charite, Pediat Clin, Berlin, Germany

[14] Johannes Gutenberg Univ Mainz, Pediat Hematol, Oncol, Hemostasiol, Mainz, Germany

[15] Univ Freiburg, Dept Pediat & Adolescent Med, Div Pediat Hematol & Oncol, Med Ctr,Fac Med, Freiburg, Germany

[16] Univ Childrens Hosp Augsburg, Swabian Childrens Canc Ctr, Augsburg, Germany

[17] Saarland Univ, Clin Pediat Oncol & Hematol, Homburg, Germany

[18] Bethel, Children Hematol & Oncol, Bielefeld, Germany

[19] Rhein Westfal TH Aachen, Fac Med, Dept Pediat Hematol Oncol & Stem Cell Transplanta, Aachen, Germany

[20] Univ Med Ctr Gottingen, Div Pediat Hematol & Oncol, Gottingen, Germany

[21] Ruprecht Karls Univ Heidelberg, Childrens Hosp, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[22] Ruprecht Karls Univ Heidelberg, Hopp Childrens Tumor Ctr, Heidelberg, Germany

[23] Klinikum Karlsruhe, Clin Children & Adolescent Med, Karlsruhe, Germany

[24] Med Univ, Pediat Hematol & Oncol, Hannover, Germany

[25] Univ Hosp Erlangen, Dept Pediat & Adolescent Med, Erlangen, Germany

[26] Univ Childrens Hosp, Dept Pediat & Pediat Hematol Oncol, Klinikum Oldenburg AoR, Oldenburg, Germany

[27] Klinikum Kassel, Clin Pediat Hematol & Oncol, Kassel, Germany

[28] Klinikum Mittelrhein, Pediat Hematol & Oncol, Koblenz, Germany

[29] Witten Herdecke Univ, Gen Pediat Oncol & Hematol, Vest Kinder & Jugendklin Datteln, Witten, Germany

[30] Klinikum Bremen, Pediat Hematol & Oncol, Bremen, Germany

[31] Univ Duisburg Essen, Pediat Hematol & Oncol, Essen, Germany

[32] Asklepios Children Clin, St Augustin, Germany

[33] Univ Childrens Hosp Muenster, Pediat Hematol & Oncol, Munster, Germany

[34] Helios Klinikum Erfurt, Clin Children & Adolescent Med, Erfurt, Germany

[35] Julius Maximilians Univ, Univ Childrens Hosp, Pediat Hematol & Oncol, Med Ctr, Wurzburg, Germany

[36] Klinikum Dortmund, Clin Children & Adolescent Med, Dortmund, Germany

[37] Clin Hallerwiese, Cnopfsche Children, Nurnberg, Germany

[38] Helios Klinikum Berlin Buch, Clin Children Hematol & Oncol, Berlin, Germany

[39] Univ Cologne, Pediat Oncol & Hematol, Cologne, Germany

[40] Tech Univ, Pediat Hematol & Oncol, Dresden, Germany

[41] Otto von Guericke Univ, Pediat Hematol & Oncol, Magdeburg, Germany

[42] Martin Luther Univ Halle Wittenberg, Fac Med, Halle, Germany

来源：

LEUKEMIA | 2020年 / 34卷 / 01期

关键词：

B-CELL LYMPHOMA; MARGINAL ZONE LYMPHOMA; REED-STERNBERG CELLS; EPSTEIN-BARR-VIRUS; SOMATIC MUTATIONS; GENETIC-HETEROGENEITY; MULTIPLE-MYELOMA; CLONAL EVOLUTION; CODING GENOME; RECURRENT;

D O I：

10.1038/s41375-019-0541-6

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：151 / 166

页数：16

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