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Oncotarget. 2016 Aug 9;7(32):51494-51502. doi: 10.18632/oncotarget.9860.

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

Author information

Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.
Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.
Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria.
Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
University Hospital of The Ludwig-Maximilians-University Munich, Medical Department III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Munich, Germany.
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.


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.


DLBCL; TP53; clonal evolution; subclonal selection; tumor heterogeneity

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Conflict of interest statement

The authors declare that they have no competing interests with regard to the content discussed in the manuscript. This work was supported by the Paracelsus Medical University (PMU Grant: E-13/17/089-MEG, R-15/03/069-MEL and E-13/18/091-EGF). The work of A.E is supported by the TRANSCAN-2 I2795 grant. OW is supported by the Max-Eder Program of the Deutsche Krebshilfe e.V. and the SFB/CRC1243 “Cancer Evolution”.

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