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The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing

Leukemia volume 28, pages 2248–2251 (2014)Cite this article

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Hodgkin lymphoma (HL) is characterized by a minority of B-cell-derived tumor cells, named Hodgkin Reed-Sternberg (HRS) cells in classical (c)HL and lymphocyte-predominant (LP) cells in nodular lymphocyte-predominant (NLP) HL. HRS cells lack expression of the B-cell receptor in most cases and rely on activation of multiple pathways to escape from apoptosis in the germinal center (GC) reaction.1 Constitutive activation of the NF-κB pathway is achieved by activation of various signaling pathways, for example, CD30, CD40-CD40L and Epstein–Barr virus (EBV)-derived latent membrane protein 1 (LMP1). In addition, NF-κB activation is caused by diverse aberrations in multiple genes involved in the NF-κB pathway, such as amplifications of REL, gains of MAP3K14, mutations of TNFAIP3, NFKBIA and NFKBIE. A second pathway frequently altered in HRS cells is the JAK/STAT signaling pathway. Activation is caused by gains of JAK2 and inactivating mutations of SOCS1. In recent years, high-throughput sequencing technology has provided novel opportunities for the comprehensive identification of genetic aberrations involved in various types of cancer. To increase our understanding of the pathogenesis of HL, we performed whole-exome sequencing (WES) in seven cell lines to identify commonly mutated genes in HL.

As a validation, we compared our WES data with the data from the Broad Institute that screened for the presence of mutations in a set of 1654 genes in five of the cell lines (Supplementary Figure S2). Inconsistencies were checked and could be explained by low read numbers probably due to ineffective capturing. Truly inconsistent variants may represent differences that have been introduced during prolonged culturing and selective outgrowth of specific subclones. The overall consistency ranged from 72.1% in L428 to 98.5% in SUPHD1 for the 1584 genes analyzed in both data sets (Supplementary Table S3). Next, we made a comparison with previously reported gene mutations in individual HL cell lines (Supplementary Table S5). With the exception of the second deletion in SOCS1 in L1236, we confirmed all mutations. By a combination of Sanger sequencing and RNA-seq data analysis we confirmed 128 out of 142 mutations shown in Figure 1b (Supplementary Table S7). Moreover, several genes previously reported to be mutated in primary cHL cases, were also mutated in the HL cell lines, for example, TNFAIP3, NFKBIE, CYLD and NFKBIA.1 More recently, PTPN1 mutations were reported at a high frequency in cHL cases and cell lines.2 Consistent with this, we observed PTPN1 gene mutations in L428 and L1236 that were not called owing to insufficient reads or strand bias. The high validation rate combined with the consistency with the Broad data and detection of mutations in genes previously reported to be mutated in HL cell lines and primary cases underscores the reliability and relevance of our WES analysis.

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Acknowledgements

We acknowledge the Genome facility of the Genetics Department (Pieter van der Vlies and others). This work was supported by grants from the Abel Tasman Talent Program, University Medical Center Groningen and the Dutch Cancer Society (KWF: RUG 2009-4313).

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Authors and Affiliations

  1. Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Y Liu, F R Abdul Razak, A Saber, L Visser, J Kluiver, A Diepstra & A van den Berg

  2. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    M Terpstra & K Kok

  3. Department of Experimental Therapeutics, Centre for Lymphoid Cancer, The BC Cancer Agency, Vancouver, British Columbia, Canada

    F C Chan, R Gascoyne & C Steidl

  4. Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    M Nijland & G van Imhoff

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  1. Y Liu
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Correspondence to A van den Berg.

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Author contributions

YL performed research, collected, interpreted data, performed statistical analyses, and wrote the manuscript; MT and FRAR performed statistical analyses, analyzed and interpreted data; AS performed data and statistical analyses; MN and GvI analyzed mutational spectrum in BL, DLBCL and FL in comparison to HL and contributed to the writing of the manuscript; LV and JK contributed samples and contributed to writing of the manuscript; FCC, RG and CS performed RNA-seq analysis, interpreted data and contributed to writing of the manuscript; AvdB, KK and AD supervised the project, designed research, interpreted data and wrote the manuscript.

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Liu, Y., Abdul Razak, F., Terpstra, M. et al. The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing. Leukemia 28, 2248–2251 (2014). https://doi.org/10.1038/leu.2014.201

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