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From genetics to the clinic: a translational perspective on follicular lymphoma

Nature Reviews Cancer volume 18, pages 224–239 (2018)Cite this article

Subjects

Key Points

  • Follicular lymphoma (FL) is a generally indolent but incurable disease characterized by multiple episodes of disease progression.

  • Cells bearing the t(14;18) translocation follow iterative transits through germinal centres upon successive immunological challenges before undergoing FL-associated developmental arrest. They accumulate deleterious genomic alterations leading to overt FL over an extended period of time (probably decades).

  • In situ follicular neoplasia and partial involvement by FL represent the earliest tumour stages identified to date.

  • Mutations in epigenetic modifiers arise in nearly 90% of patients with FL and likely represent an early event in lymphomagenesis. Survival pathways such as B cell receptor (BCR), mTOR complex 1 (mTORC1) or Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling, as well as proteins implicated in escape from immune surveillance, are also frequently affected by mutations.

  • Disease progression and histological transformation exhibit different clonal dynamics that are driven by distinct evolutionary mechanisms. The acquisition of a transformed phenotype through divergent evolution might not be predictable at the time of diagnosis.

  • In addition to immunotherapy, inhibitors of methyltransferases, histone deacetylases, the BCR signalling pathway and mTORC1 represent potential therapeutic options being investigated.

Abstract

Follicular lymphoma (FL) is the most frequent indolent B cell lymphoma and is still considered to be incurable. In recent years, whole-exome sequencing studies of large cohorts of patients have greatly improved our knowledge of the FL mutational landscape. Moreover, the prolonged evolution of this disease has enabled some insights regarding the early pre-lymphoma lesions as well as the clonal evolution after treatment, allowing an evolutionary perspective on lymphomagenesis. Deciphering the earliest initiating lesions and identifying the molecular alterations leading to disease progression currently represent important goals; accomplishing these could help identify the most relevant targets for precision therapy.

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Figure 1: Early steps of follicular lymphomagenesis.
Figure 2: The many layers of epigenetic dysregulation in FL.
Figure 3: Signals driving proliferation and survival of FL cells.
Figure 4: Genomic alterations subverting microenvironment.
Figure 5: Clonal dynamics of relapse.

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Authors and Affiliations

  1. Cancer Research Center of Lyon, INSERM 1052 CNRS5286, 'Clinical and experimental models of lymphomagenesis' Team, Equipe labellisée Ligue Contre le Cancer Oullins, France

    Sarah Huet, Pierre Sujobert & Gilles Salles

  2. Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, 165 chemin du Grand Revoyet, Pierre Bénite, 69495, France

    Sarah Huet, Pierre Sujobert & Gilles Salles

  3. Université Lyon-1, ISPB-Faculté de Pharmacie de Lyon, Lyon, France

    Sarah Huet

  4. Université Lyon-1, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Oullins, France

    Pierre Sujobert & Gilles Salles

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  1. Sarah Huet
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S.H., P.S. and G.S. researched data for the article, made substantial contributions to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Gilles Salles.

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PowerPoint slides

Glossary

Germinal centres

(GCs). Histological structures of secondary lymphoid tissues (lymph nodes, spleen and mucosa-associated lymphoid tissue) where B cells encounter antigens in the B cell follicles. The GC reaction is a complex cascade of events coordinated to allow the generation, selection and expansion of B cells secreting high-affinity antibodies through somatic hypermutation of the immunoglobulin genes. B cells with the highest affinity for antigen are positively selected and undergo class-switch recombination.

Activation-induced cytidine deaminase

(AID). A deaminase expressed in germinal centre B cells that catalyses the deamination of cytosine to uracil, thereby initiating mutations in DNA sequence and double-strand DNA breaks. It is responsible for somatic hypermutation and class-switch recombination.

VDJ recombination

A genetic mechanism that recombines the variable (V), diversity (D) and joining (J) regions of the immunoglobulin heavy chain loci, which leads to repertoire diversity of B cell receptors.

Follicular lymphoma-like cells

(FLLCs). Germinal centre-derived memory B cells bearing t(14;18) that are found in healthy individuals. These cells are developmentally blocked, with a centroblast-like or centrocyte-like phenotype and ongoing activation-induced cytidine deaminase and B cell lymphoma 6 protein activity. They likely have not yet acquired the additional genetic hit(s) allowing progression to follicular lymphoma.

Memory B cells

Antigen-experienced B cells that express high-affinity antibodies and can promptly differentiate into plasma cells following antigen recall.

Centroblast

A proliferating B cell found in the dark zone of germinal centres that experiences ongoing somatic hypermutation of the rearranged variable region immunoglobulin genes.

Centrocyte

The progeny of a centroblast, this cell is found in the light zone of germinal centres. The immunoglobulin from these cells is tested for antigen affinity. High-affinity centrocytes can be selected to undergo immunoglobulin class switching and for further differentiation into memory B cells or plasma cells.

Allelic paradox

Describes the paradoxical genotypic and immunophenotypic features of most follicular lymphoma tumours in which a surface immunoglobulin M is expressed despite class-switch recombination occurring on both IGH alleles. A μ/γ switch is observed on the IGH constant region of the translocated allele, and an abnormal downstream γ/γ or γ/α switch is observed on the functional allele, selectively sparing the Cμ region.

Class-switch recombination

A genetic mechanism by which antigen-activated B cells change the constant region of their immunoglobulin (or isotype) to generate antibodies with different effector functions.

Committed follicular lymphoma precursors

Cells carrying the t(14;18) translocation in healthy individuals who have been observed to progress to follicular lymphoma. This definition still varies between authors and needs a consensus in the scientific community.

B cell receptor

(BCR). The surface receptor for antigens in mature B cells. A functional BCR is composed of a combination of two identical heavy chain and two identical light chain immunoglobulin polypeptides and is associated with cytoplasmic molecules that deliver downstream signalling. This signalling has emerged as a central oncogenic pathway that promotes growth and survival in various lymphoma types.

Common progenitor cell

(CPC). Putative cells containing a shared set of mutations and alterations inferred either from intratumoural heterogeneity or from paired samples (for example, diagnosis and relapse or lymph node and bone marrow). This definition still varies between authors and needs a consensus in the scientific community.

Diffuse large B cell lymphoma

(DLBCL). The most frequent type of B cell non-Hodgkin lymphoma in adults, with a generally aggressive clinical course. It can be primitive or develop following transformation of an indolent type of lymphoma. Several subtypes are defined based on morphology, anatomical site or molecular features.

Somatic hypermutation

A genetic mechanism that introduces mainly single-nucleotide mutations into the variable regions of the immunoglobulin genes. This process is mediated by the enzyme activation-induced cytidine deaminase in germinal centre B cells and may alter the affinity or specificity of the immunoglobulin receptor for antigen.

VavP–BCL2 mouse model

A transgenic mouse model in which human BCL2 is overexpressed under the control of the pan-haematopoietic VavP promoter and thus expressed in cells of all haematopoietic lineages. Approximately half of these mice develop follicular lymphoma.

Follicular lymphoma international prognostic index

(FLIPI). A clinical score evaluating patient prognosis at the time of follicular lymphoma diagnosis.

Performance status

Describes a patient's daily living abilities. Standard criteria might be used to measure how a disease impacts these abilities. The Eastern Cooperative Oncology Group (ECOG) scale of performance status is widely used in oncology.

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Huet, S., Sujobert, P. & Salles, G. From genetics to the clinic: a translational perspective on follicular lymphoma. Nat Rev Cancer 18, 224–239 (2018). https://doi.org/10.1038/nrc.2017.127

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