Genomic Discovery, Prognosis, and Target Therapy Development
Authors: Fitzgibbon Jude 
Published: October 2019

For over three decades now, the t(14;18)(q32.3;q21.3) has been synonymous with the indolent B cell malignancy, follicular lymphoma (FL). Through the widespread uptake of next generation sequencing, we recognize that these tumors acquire many additional genetic aberrations, targeting several distinct signaling pathways (HVEM, mTORC1, NOTCH, NF-κB and JAK-STAT) all of which fall onto a backbone of epimutations that arise in nearly all FL tumors and preferentially target the histone methyl (KMT2D) and acetyl (CREBBP) transferase machinery. We are still in the early stages of understanding how these mutations impact on the biology of FL, their weight of contribution to FL initiation, progression and transformation and indeed whether we can harness this new knowledge to improve on existing treatment. At the very least, we now realize that the acquisition of these mutations and onset of FL may occur several years earlier from the study of rare examples of clonally-related tumors developing post bone marrow transplantation in both donor and recipient. This has helped formulate the notion of an uncharacterized common progenitor pool of B cells (CPC) that are capable of seeding each new genetically distinct episode of disease and providing an explanation for the relapsing remitting nature of FL. We can also now infer the nature of the apparent early driver mutations that seemingly propagate the disease in all FL clones, including the CPC, by using a gene's mutation load or clonal composition as a surrogate marker. It is apparent that many epimutations represent early events and appear to alter normal B cell programming by favoring sets of genes that promote proliferation and survival while switching off anti-tumor mechanisms, with CREBBP-mutated FLs for example showing a decreased antigen presentation gene signature. The prospect of following a precision medicine approach informed by a patient's mutation composition should be encouraged given the frequency of activating EZH2 mutations, an underappreciated role of the NF-κB pathway and mutations in the mTORC1 pathway, that are unique to FL, together with the availability of targeted therapeutic agents. There is of course a need to focus efforts on the 20% of patients that succumb to early disease relapse, and the emergence of a new clinical-genetic risk model (m7-FLIPI), as an outcome predictor offers a promising first step in developing a robust risk stratification approach. We do however need to embrace these new opportunities and embed biomarker discovery and validation studies as part of all FL trial programs. Indeed, a case can be made for utilizing material from specific retrospective studies, where updated mutation analysis may demonstrate a potential novel predictive and therapeutic biomarker (e.g. RRAGC mutations/mTOR inhibitors). Altogether, while the genetic portrait of FL is still far from complete, we are now much closer to delivering a final canvas and with it the prospect of changing the landscape of future FL treatment.

Disclosures

Fitzgibbon: Epizyme: Research Funding; Gilead: Honoraria; Janssen: Honoraria; Celgene: Honoraria.