Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

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.

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

“…We used the Mb1-cre for deletion of Crebbp at an early stage of B-cell development because BCL2 translocation in human lymphoma is thought to be acquired as a byproduct of faulty VDJ recombination in pre-or pro-B cells. 36 We observed that CREBBP mutations occur as an early secondary event in FL, 14 which has been validated in subsequent studies, 12 and we therefore speculate that this may also occur at an early stage of B-cell development. Inactivation of Crebbp was associated with marked reductions in the frequencies of multiple B-cell subsets in both young and adult mice, in line with prior observations that loss of Crebbp with a Cd19-cre resulted in ;50% loss in peripheral B cells.…”

“…2 We and others have shown that CREBBP mutations are early events in the clonal evolution of FL and are maintained in the tumor at progression and transformation. 9,10,12,14,23 In addition, we showed that CREBBP point mutations in FL are associated with a marked downregulation of major histocompatibility complex (MHC) class II expression and may therefore drive immune evasion. 14 Other studies have shown that CREBBP mutations in DLBCL may drive disease pathogenesis through the deregulation of BCL6 or TP53 function.…”

Can histologic transformation of follicular lymphoma be predicted and prevented?

“…51,53 In our own work, we found that FL cases with subsequent transformation had higher numbers of structural rearrangements as compared with cases experiencing either progression in the absence of transformation, or cases who were event-free for at least 5 years following diagnosis. 24 These findings clearly suggest that genome-wide discovery approaches hold great potential for uncovering genomic properties of rapid transformation.…”

“…[19][20][21][22][23] On the molecular level, transformed FL (TFL) differs from preceding indolent FL by higher numbers of single-nucleotide mutations, small insertions and deletions, copy-number changes, and structural rearrangements. [24][25][26] Transformation occurs via the activation of known or putative oncogenes (MYC, CCND3) and inactivation of known or putative tumor suppressor genes (TP53, CDKN2A/B, B2M). [26][27][28][29][30][31][32][33][34][35] Recent genome-wide studies have contributed to expanding our knowledge on the breadth of genetic alterations that are associated with transformation.…”

“…64 The FL tumor microenvironment has received well-deserved attention by numerous studies. Nonneoplastic immune and stromal cells clearly play an important role in the pathogenesis of FL, as evidenced by the influence that recurrent genetic alterations exert on the composition of the tumor microenvironment, 24,65,66 and by the association between immune cell-related gene expression changes and overall survival. 67 Glas et al performed gene expression and immunohistochemical analyses of samples from 31 patients with rapid transformation and 35 patients without transformation.…”