T008 (0050) GENOTYPING CIRCULATING TUMOR DNA OF PEDIATRIC HODGKIN LYMPHOMA PATIENTS TO DETERMINE PATHOGENIC MECHANISMS AND MONITOR THERAPY

doi: 10.1097/01.HS9.0000547852.20772.3c
Biology and Microenvironment
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Andreas Bräuninger1, Ann-Kathrin Desch1, Kristin Kunze1, Ante Boten2, Alexander Brobeil1, Mathias Rummel3, Lars Kurch4, Thomas Georgi4, Regine Kluge4, Christine Mauz-Körholz2, Dieter Körholz2, Stefan Gattenlöhner1

1Institute of Pathology,2Department of Pediatric Oncology and Hematology,3Hematology, Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany,4Clinic for Nuclear Medicine, University of Leipzig, Leipzig, Germany

We used hybrid capture based targeted next generation sequencing of 106 genes and genomic regions frequently affected by mutations and translocations in B cell lymphomas to detect somatic variants in circulating cell free DNA (ccfDNA) of pediatric Hodgkin lymphoma patients.Somatic variants, including 11 translocation breakpoints, were detected in 69 of 94 samples with 1–13 variants per sample and allele frequencies from 1–36%. Fragments of clonotypic VH-DH-JH rearrangements were captured from 16 samples. For all 22 variants, 5 translocation breakpoints and 5 VH-DH-JH rearrangements of 16 cases tested an origin from Hodgkin-Reed/Sternberg (HRS) cells could be demonstrated. Compared to genomic DNA from biopsies and blood cells ccfDNA was superior for detection of HRS genomic variants. Genes involved in JAK/STAT signalling, NFkB regulation, antigen presentation and PIK3 signalling were most frequently affected. 9 of 11 translocations involved SOCS1 and all caused SOCS1 inactivation. EBV status or histological subtype was not related to amounts of circulating tumor DNA. Analysis of the VH-DH-JH rearrangements revealed an origin from germinal center experienced but unselected B cells. Amount of tumor DNA in pre-therapy ccfDNA was related to metabolic tumor volume but not to stage or early response to chemotherapy. In consecutive ccfDNA samples of 19 patients responding to chemotherapy all 61 variants fall already after the first cycle below the detection limit and remained there in all further 34 samples from later time-points. In contrast, in 3 poor-responding cases mutations remained detectable, at least after the first or second chemotherapy cycle. ccfDNA of pediatric Hodgkin lymphoma is thus a suitable source to determine pathogenic mechanisms and monitor therapy already at early timepoints.

Copyright © 2018 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.