Date Published: December 13, 2016
Publisher: Public Library of Science
Author(s): Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A. Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew Mungall, Richard Moore, Ryan D. Morin, Nathalie A. Johnson, Laurie H. Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M. Connors, David W. Scott, Christian Steidl, Marco A. Marra, Randy D. Gascoyne, Sohrab P. Shah, Elaine Rene Mardis
Abstract: BackgroundFollicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Methods and FindingsUsing a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.ConclusionsOur results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
Partial Text: Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma and the most frequent indolent lymphoma, accounting for 22%–32% of all new non-Hodgkin lymphoma diagnoses in Western countries [1,2]. Patient outcomes are favorable, with median overall survival extending well beyond 10 y [3–5]. However, FL remains an incurable malignancy as most patients eventually experience progressive disease. A subset of patients are at risk of early lymphoma-related mortality due to early progression after immunochemotherapy or to histological transformation to aggressive lymphoma (2%–3% of patients per year), both of which lead to shortened survival [6–13]. Hence, mutational profiling of FL specimens at the temporal boundaries of clinical inflection points represents a compelling opportunity to study the evolutionary dynamics underpinning FL disease progression.
We established that transformation and progression in FL are driven by disparate modes of evolutionary change. Shown schematically in Fig 10, TFL is characterized by the emergence of clones that become dominant at T2 and that typically lie below the detection limit of even highly sensitive methods at the T1 (FL) time point (Fig 10A), implying that the aggressive phenotypes emerge after diagnosis. By contrast, early progression of FL commonly results from prevalent clones at T1, such that much of the clonal architecture is maintained despite treatment, implying that resistant properties are well established at diagnosis (Fig 10B). The content of gene mutations associated with transformation and early progression also differed. We found novel associations of gene mutations with transformation (including CCND3, GNA13, S1PR2, and P2RY8 mutations) and showed that TFL is molecularly heterogeneous, with, for example, the ABC subtype of TFL being enriched for BCL10, CD79B, and MYD88 mutations. Genes with recurrent mutations associated with early progression included KMT2C, TP53, BTG1, and MKI67. Thus, transformation and progression can be attributed to disruption of different biological processes.