Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones.
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.
Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.|Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Thomas
T
Melchardt
Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.|Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Clemens
C
Hufnagl
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
David M
DM
Weinstock
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nadja
N
Kopp
Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria.
Daniel
D
Neureiter
Institute of Pathology, Paracelsus Medical University Salzburg, Salzburg, Austria.
Wolfgang
W
Tränkenschuh
Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Hubert
H
Hackl
Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.|Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Lukas
L
Weiss
Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.|Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Gabriel
G
Rinnerthaler
Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.|Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Tanja N
TN
Hartmann
Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.|Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Richard
R
Greil
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.
Oliver
O
Weigert
Third Medical Department at The Paracelsus Medical University Salzburg, Salzburg, Austria.|Salzburg Cancer Research Institute (SCRI), Salzburg, Austria.|Cancer Cluster Salzburg (CCS), Salzburg, Austria.
Alexander
A
Egle
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060965:Clonal Evolution / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology*; D017211:Treatment Failure; D055815:Young Adult
DLBCL; TP53; clonal evolution; subclonal selection; tumor heterogeneity