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

Abstract

BackgroundMolecular 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.ResultsWe 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.ConclusionsAltogether, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0432-0) contains supplementary material, which is available to authorized users.

Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas

“…Our data confirm the work by Jiang and colleagues who showed that clonal evolution occurs in DLBCL under the selection pressure of RCHOP and subsequent therapies, by showing clonal enrichment of one or more mutation in 11 of 12 paired samples (19). A repeat biopsy at the time of relapse would therefore be warranted if the tumor biology were guiding the choice of therapy.…”

“…Our work directly complements previous studies of rrDLBCL that were underpowered to detect mutations that were significantly more common at relapse (19,20). TP53 emerged as a top candidate in our analyses, an expected result that supports our analytic approach.…”

“…Given that very few patients survive rrDLBCL, there is also a lack of constitutional DNA for most archived samples, which is important to exclude germline variants when performing wholeexome sequencing (WES). For such reasons, the genomic profile of rrDLBCL is not well known, with two small cohorts of approximately 10 patients described in the literature to date (19,20). Characterizing a sufficient number of rrDLBCL samples may lead to insights into the genetic events that lead to therapeutic resistance and reveal pathways that are consistently activated at relapse, some of which may be targeted with existing or novel therapies.…”

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

“…10 There is typically a clonal evolution among lymphoma cells, with some heterogeneity of genes involved in lymphoma growth that might explain the chemorefractoriness and difficulties of salvage. 11 Furthermore, it has also been shown that DLBCL pathogenesis is strongly related to epigenetic perturbations and that high epigenomic heterogeneity correlated with a higher relapse rate and poor outcome. 12 These observations open the pathway to specific DNA methyltransferase and histone methyltransferase inhibitors designed to erase aberrant epigenetic programming.…”

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

“…All targeted sequencing raw data files, including VDJsequencing and targeted resequencing of the UBR4 and B2M loci, have been deposited into NBCI database BioProject PRJNA240336 [50].…”