Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones
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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
Alexander Egle, email: firstname.lastname@example.org
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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