Research Papers:

Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones

Thomas Melchardt, Clemens Hufnagl, David M. Weinstock, Nadja Kopp, Daniel Neureiter, Wolfgang Tränkenschuh, Hubert Hackl, Lukas Weiss, Gabriel Rinnerthaler, Tanja N. Hartmann, Richard Greil, Oliver Weigert and Alexander Egle _

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Oncotarget. 2016; 7:51494-51502. https://doi.org/10.18632/oncotarget.9860

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Thomas Melchardt1,2,3,*, Clemens Hufnagl1,2,3,*, David M. Weinstock4, Nadja Kopp4, Daniel Neureiter5, Wolfgang Tränkenschuh5, Hubert Hackl6, Lukas Weiss1,2,3, Gabriel Rinnerthaler1,2,3, Tanja N. Hartmann1,2,3, Richard Greil1,2,3 Oliver Weigert7,8, Alexander Egle1,2,3

1Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria

2Salzburg Cancer Research Institute (SCRI), Salzburg, Austria

3Cancer Cluster Salzburg (CCS), Salzburg, Austria

4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

5Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria

6Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

7University Hospital of The Ludwig-Maximilians-University Munich, Medical Department III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Munich, Germany

8German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

*These authors have contributed equally to this work

Correspondence to:

Alexander Egle, email: [email protected]

Keywords: DLBCL, clonal evolution, TP53, tumor heterogeneity, subclonal selection

Received: November 18, 2015     Accepted: May 22, 2016     Published: June 06, 2016


Little information is available about the role of certain mutations for clonal evolution and the clinical outcome during relapse in diffuse large B-cell lymphoma (DLBCL). Therefore, we analyzed formalin-fixed-paraffin-embedded tumor samples from first diagnosis, relapsed or refractory disease from 28 patients using next-generation sequencing of the exons of 104 coding genes. Non-synonymous mutations were present in 74 of the 104 genes tested. Primary tumor samples showed a median of 8 non-synonymous mutations (range: 0-24) with the used gene set. Lower numbers of non-synonymous mutations in the primary tumor were associated with a better median OS compared with higher numbers (28 versus 15 months, p=0.031). We observed three patterns of clonal evolution during relapse of disease: large global change, subclonal selection and no or minimal change possibly suggesting preprogrammed resistance. We conclude that targeted re-sequencing is a feasible and informative approach to characterize the molecular pattern of relapse and it creates novel insights into the role of dynamics of individual genes.

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