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. 2017 Nov 30;8(67):111386-111395.
doi: 10.18632/oncotarget.22799. eCollection 2017 Dec 19.

Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets

Elena Mata  1 , Antonio Díaz-López  1 , Ana M Martín-Moreno  1 , Margarita Sánchez-Beato  2 , Ignacio Varela  3 , María J Mestre  4 , Carlos Santonja  5 , Fernando Burgos  6 , Javier Menárguez  7 , Mónica Estévez  8 , Mariano Provencio  2 , Beatriz Sánchez-Espiridión  9 , Eva Díaz  1 , Carlos Montalbán  8 , Miguel A Piris  5 , Juan F García  1
Affiliations

Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets

Elena Mata et al. Oncotarget. .

Abstract

Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells. Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others. This unexpectedly high prevalence of mutations affecting the BCR pathway suggests some requirement for active BCR signaling for cHL cell viability. Additionally, incubation of a panel of cHL cellular models with selective BTK inhibitors in vitro constrains cell proliferation and causes cell death. Our results indicate new pathogenic mechanisms and therapeutic opportunities in this disease.

Keywords: B-cell receptor; BTK; Hodgkin lymphoma; mutational analysis; therapeutic target.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Mutational landscape
The diagram shows the distribution of gene variants. 40.3% of samples have at least 1 SNV after filtering. We identified variants in 66.6% of the selected genes. One SNV is indicated in red, while genes with more than two SNVs are indicated in dark red. The final two columns indicate the number and percentage of mutated genes per case. The bottom two rows indicate the number and percentage of cases with at least one SNV.
Figure 2
Figure 2. Mutational landscape in 6 cHL-derived cell lines and Sanger sequencing validation
(A) The diagram shows the distribution of mutations per cell line. One SNV is indicated in red, while two SNVs per gene are indicated in dark red. Black boxes correspond to SNVs validated by Sanger sequencing. (B) Representative example, CARD11 mutation in the KMH2 cell line; IGV diagram (Ion Torrent sequencing) and Sanger sequencing representation.
Figure 3
Figure 3. Functional studies in cHL-derived and DLBCL-derived cell lines
(A) Western blot analysis of total BTK, CYLD truncation, NFKB (p52 isoform), and phospho-IkBα. (B and C) Activity of BTK selective inhibitors in cHL-derived and DLBCL-derived cell lines. IC50 range calculation of HBL1, HDLM2, L540, and L1236 cell lines in the presence of different concentrations of Ibrutinib or AVL-292, after 48 hours.
Figure 4
Figure 4. Btk IHC expression in HRS cells and Its correlation with survival
(A) Representative examples of IHC for Btk expression in cHL tissues. (B) Distribution of Btk protein expression in our series. Positivity (+) was concluded for cases with a level of expression comparable to that seen in normal germinal center B lymphocytes. (C) Kaplan–Meier survival curves demonstrate longer FFS in wt-BTK cases (P<0.05). (D) Survival curves demonstrate a longer FFS in cases with a low level of expression of Btk protein (P=n.s.).
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