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

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.

Clonal evolution in relapsed and refractory diffuse large B-cell lymphoma is characterized by high dynamics of subclones

“…The three major patterns of clonal evolution we describe (see Figure 2 and 5) are paralleled in a recent study using VDJ rearrangement to track evolution in 14 matched samples of primary and relapsed DLBCL. These authors proposed an early-divergent and a late-divergent mode of clonal evolution [17], similar to our classification. Importantly, our data make it seem difficult to envision appropriate tools to predict the mechanisms of clonal evolution from the baseline sample in the near future.…”

Late relapse in patients with diffuse large B‐cell lymphoma: impact of rituximab on their incidence and outcome

“…We can confirm that indolent relapses are not rare and that a biopsy should be mandatory at the time of disease recurrence. It is possible that indolent relapse represents the reappearance of the indolent component of a misdiagnosed composite lymphoma, although the hypothesis of a second lymphoma could not be excluded without molecular studies (Nishiuchi et al, 1996;Head et al, 1988;Jiang et al, 2014;Juskevicius et al, 2016;Juskevicius et al, 2017;Rizzo et al, 2017). However, the question of whether late relapses represent a clonally-related or a de novo lymphoma, is still matter of ongoing debate and only few data exist on their biology.…”

The Epigenetic Basis of Diffuse Large B-Cell Lymphoma

“…DLBCLs tend to have heavy mutation burdens and exhibit considerable intratumoral heterogeneity. Yet mutation of epigenetic modifiers tend to be widely distributed among lymphoma cells in individual patients suggesting that they occur at early stages of lymphomagenesis [27-29]. We present views on the most frequently mutated epigenetic modifiers in DLBCL which are EZH2, EP300, CREBBP and KMT2D (also known as MLL4 or MLL2, Figure 2).…”