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Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

Yanwen Jiang12, David Redmond1, Kui Nie3, Ken W Eng1, Thomas Clozel4, Peter Martin2, Leonard HC Tan5, Ari M Melnick2, Wayne Tam3* and Olivier Elemento1*

Author Affiliations

1 Institute for Computational Biomedicine, Weill Cornell Medical College, New York 10021, NY, USA

2 Department of Medicine, Weill Cornell Medical College, New York 10021, NY, USA

3 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York 10021, NY, USA

4 Hematology, Lymphoid Unit, Hôpital Henri Mondor, Creteil 94010, France

5 Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore

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Genome Biology 2014, 15:432  doi:10.1186/s13059-014-0432-0

Published: 15 August 2014

Abstract

Background

Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question.

Results

We performed high-throughput sequencing of rearranged VDJ junctions in 14 pairs of matched diagnosis-relapse tumors, among which 7 pairs were further characterized by exome sequencing. We identify two distinctive modes of clonal evolution of DLBCL relapse: an early-divergent mode in which clonally related diagnosis and relapse tumors diverged early and developed in parallel; and a late-divergent mode in which relapse tumors developed directly from diagnosis tumors with minor divergence. By examining mutation patterns in the context of phylogenetic information provided by VDJ junctions, we identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events.

Conclusions

Altogether, our study for the first time provides important evidence that DLBCL relapse may result from multiple, distinct tumor evolutionary mechanisms, providing rationale for therapies for each mechanism. Moreover, this study highlights the urgent need to understand the driving roles of epigenetic modifier mutations in lymphomagenesis, and immune surveillance factor genetic lesions in relapse.