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. 2018 Nov 20;10(11):459.
doi: 10.3390/cancers10110459.

Mutational Evolution in Relapsed Diffuse Large B-Cell Lymphoma

Marcel Nijland  1 , Annika Seitz  2 , Martijn Terpstra  3 , Gustaaf W van Imhoff  4 , Philip M Kluin  5 , Tom van Meerten  6 , Çiğdem Atayar  7 , Léon C van Kempen  8 , Arjan Diepstra  9 , Klaas Kok  10 , Anke van den Berg  11
Affiliations

Mutational Evolution in Relapsed Diffuse Large B-Cell Lymphoma

Marcel Nijland et al. Cancers (Basel). .

Abstract

Current genomic models in diffuse large B-cell lymphoma (DLBCL) are based on single tumor biopsies, which might underestimate heterogeneity. Data on mutational evolution largely remains unknown. An exploratory study using whole exome sequencing on paired (primary and relapse) formalin fixed paraffin embedded DLBCL biopsies (n = 14) of 6 patients was performed to globally assess the mutational evolution and to identify gene mutations specific for relapse samples from patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. A minority of the mutations detected in the primary sample (median 7.6%, range 4.8⁻66.2%) could not be detected in the matching relapse sample. Relapsed DLBCL samples showed a mild increase of mutations (median 12.5%, range 9.4⁻87.6%) as compared to primary tumor biopsies. We identified 264 genes possibly related to therapy resistance, including tyrosine kinases (n = 18), (transmembrane) glycoproteins (n = 73), and genes involved in the JAK-STAT pathway (n = 7). Among the potentially resistance related genes were PIM1, SOCS1, and MYC, which have been reported to convey a risk for treatment failure. In conclusion, we show modest temporal heterogeneity between paired tumor samples with the acquisition of new mutations and identification of genes possibly related to therapy resistance. The mutational evolution could have implications for treatment decisions and development of novel targeted drugs.

Keywords: diffuse large B-cell lymphoma; evolution; fresh frozen paraffin embedded; heterogeneity; mutations; relapse.

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Conflict of interest statement

The authors declare that they have no conflicts of interest regarding this paper.

Figures

Figure 1
Figure 1
Frequency of mutations in the top-20 most commonly mutated genes in diffuse large B-cell lymphoma according to the Cosmic database version 86, and as observed in the 14 tumor samples analyzed in this study. Fourteen of the 20 genes were mutated in at least one of the 14 samples. SOC1 and PIM1 mutations were observed in 5 of 6 patients.
Figure 2
Figure 2
Venn diagrams showing for each individual patient (P1–6) the overlap in mutations between primary and paired relapse tumor samples. Left panels are Venn diagrams for all mutations (all), and right panels are Venn diagrams for mutations with a mutant allele frequency (MAF) ≥0.2. The total numbers of mutations per patient are depicted below each diagram. The size of the relapse diagram is proportional to the primary sample. In the patients with two biopsies at relapse (P5 and P6), the concordance between the novel mutations in the relapse samples was 45.3% and 89.2%, indicative of spatial heterogeneity.
Figure 3
Figure 3
Graphical representation of mutant allele frequency (MAF) of (A) SOCS1, (B) PIM1, and (C) MYC in paired biopsies. Mutations above the dashed line are considered as possibly related to therapy resistance. The MAF of SOCS1 mutations remains relatively stable. The MAF of mutations in PIM1 and MYC had at least a two-fold increase in 2 of 5 and 2 of 3 patients, respectively.
See this image and copyright information in PMC

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