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Cytogenetics and molecular genetics

Distinct genetic evolution patterns of relapsing diffuse large B-cell lymphoma revealed by genome-wide copy number aberration and targeted sequencing analysis

Abstract

Recurrences of diffuse large B-cell lymphomas (DLBCL) result in significant morbidity and mortality, but their underlying genetic and biological mechanisms are unclear. Clonal relationship in DLBCL relapses so far is mostly addressed by the investigation of immunoglobulin (IG) rearrangements, therefore, lacking deeper insights into genome-wide lymphoma evolution. We studied mutations and copy number aberrations in 20 paired relapsing and 20 non-relapsing DLBCL cases aiming to test the clonal relationship between primaries and relapses to track tumors’ genetic evolution and to investigate the genetic background of DLBCL recurrence. Three clonally unrelated DLBCL relapses were identified (15%). Also, two distinct patterns of genetic evolution in clonally related relapses were detected as follows: (1) early-divergent/branching evolution from a common progenitor in 6 patients (30%), and (2) late-divergent/linear progression of relapses in 11 patients (65%). Analysis of recurrent genetic events identified potential early drivers of lymphomagenesis (KMT2D, MYD88, CD79B and PIM1). The most frequent relapse-specific events were additional mutations in KMT2D and alterations of MEF2B. SOCS1 mutations were exclusive to non-relapsing DLBCL, whereas primaries of relapsing DLBCL more commonly displayed gains of 10p15.3–p12.1 containing the potential oncogenes PRKCQ, GATA3, MLLT10 and ABI1. Altogether, our study expands the knowledge on clonal relationship, genetic evolution and mutational basis of DLBCL relapses.

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Acknowledgements

This study was supported by Krebsliga beider Basel and Stiftung zur Krebsbekämpfung Zürich. We thank Sibylle Tschumi, Tanja Dietsche, David Jucker, Luca Quagliata and Bruno Grilli for their help in performing NGS and FISH investigations. The chromosomal copy number aberration data reported in this paper has been deposited at the National Center for Biotechnology Information Gene Expression Omnibus (accession no. GSE65720). The targeted sequencing data has been deposited to Sequence Read Archive (accession no. SRP067323).

Author contributions

DJ performed the research, analyzed and interpreted the data, and wrote the manuscript; JG, CR and TL analyzed the data and revised the manuscript; VP contributed to sequencing analysis; FS-L analyzed the clinical data and revised the manuscript; SD performed histological and immunohistochemical analysis, revised the manuscript; AT conceived and designed the study, performed histological, immunohistochemical and FISH analysis, analyzed and interpreted the data, and revised the manuscript.

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Correspondence to A Tzankov.

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Juskevicius, D., Lorber, T., Gsponer, J. et al. Distinct genetic evolution patterns of relapsing diffuse large B-cell lymphoma revealed by genome-wide copy number aberration and targeted sequencing analysis. Leukemia 30, 2385–2395 (2016). https://doi.org/10.1038/leu.2016.135

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