Pathogenesis of follicular lymphoma: genetics to the microenvironment to clinical translation

Follicular lymphoma (FL) represents a heterogeneous disease both clinically and biologically. The pathognomonic t(14;18) translocation can no longer be thought of as the primary genetic driver, with increasing recognition of the biological relevance of recurrent genetic alterations in epigenetic regulators that now feature as a pivotal hallmark of this lymphoma subtype. Furthermore, sequencing studies have provided a near complete catalogue of additional genetic aberrations. Longitudinal and spatial genetic studies add an additional layer to the biological heterogeneity, providing preliminary molecular insights into high-risk phenotypes such as early progressors and transformation, and also supporting evidence for the existence of persisting re-populating cells that act as lymphoma reservoirs and harbingers for FL recurrence. Simultaneously, understanding of the tumour microenvironmental cues promoting lymphomagenesis and disease progression continue to broaden. More recently, studies are beginning to unravel the convergence and co-operation between the genetics, epigenetics and microenvironment. There is a pressing need to marry biology with therapeutics, especially with the burgeoning treatment landscape in FL, to aid in optimising patient selection and guiding the 'right drug to the right patient'.