Liquid biopsy in lymphoma: Is it primed for clinical translation?

The simultaneous growth in our understanding of lymphoma biology and the burgeoning therapeutic options has come with a renewed drive for precision-based approaches and how best to incorporate them into contemporary and future patient care. In the hunt for accurate and sensitive biomarkers, liquid biopsies, particularly circulating tumour DNA, have come to the forefront as a promising tool in multiple cancer types including lymphomas, with considerable implications for clinical practice. Liquid biopsy analyses could supplement existing tissue biopsies with distinct advantages including the minimally invasive nature and the ease with which it can be repeated during a patient's clinical journey. Circulating tumour DNA (ctDNA) analyses has been and continues to be evaluated across lymphoma subtypes with potential applications as a diagnostic, disease monitoring and treatment selection tool. To make the leap into the clinic, these assays must demonstrate accuracy, reliability and a quick turnaround to be employed in the real-time clinical management of lymphoma patients. Here, we review the available ctDNA assays and discuss key practical and technical issues around improving sensitivity. We then focus on their potential roles in several lymphoma subtypes exemplified by recent studies and provide a glimpse of different features that can be analysed beyond ctDNA

Genetic heterogeneity in follicular lymphoma

The genetic underpinnings of follicular lymphoma (FL) are now better understood through sequencing efforts of the last decade. Epigenetic deregulation, particularly through mutations in chromatin-modifying enzymes, is recognised as a pivotal hallmark that occurs alongside the t(14;18) chromosomal translocation, together with mutations in genes that affect a number of secondary biological pathways including mTORC1, JAK-STAT, NF-kB signalling and immune evasion. In recent years, the functional relevance of these genetic aberrations has been independently deciphered. The protracted nature of FL has provided an excellent model to chart the heterogeneity and evolution of the genetic features of the lymphomas both temporally and spatially. These studies have pointed to the early and late genetic drivers of the disease and the existence of a putative reservoir population that is difficult to eradicate with conventional treatment and most likely contributes to the relapsing-remitting nature of FL. Additionally, these sequencing studies have identified similarities and distinct differences in the genetic profiles of FL compared to related histological entities. In this review, we aim to summarise the current state of our understanding of the genetic landscape and heterogeneity, its contribution to the spectrum of clinical phenotypes in FL and related entities and finally, the ongoing efforts to utilise biology to provide lines of sight to the clinic

Precision medicine and lymphoma

Cancer Research UK (15968 awarded to J.F., 22742 awarded to J.O.) and Bloodwise program grant [15002] through the Precision Medicine for Aggressive Lymphoma (PMAL) consortium. E.A.K. is in receipt of fellowship funding from The Medical College of Saint Bartholomew’s Hospital Trust. J.F. declares grants from Epizyme and personal fees from Roche, Gilead, Janssen and Epizyme

Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA)

Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA)

Personalised therapy in follicular lymphoma - is the dial turning?

Follicular lymphoma is the most common indolent lymphoma accounting for approximately 20%–25% of all new non-Hodgkin lymphoma diagnoses in western countries. Whilst outcomes are mostly favorable, the spectrum of clinical phenotypes includes high-risk groups with significantly inferior outcomes. This review discusses recent updates in risk stratification and treatment approaches from upfront treatment for limited and advanced stage follicular lymphoma to the growing options for relapsed, refractory disease with perspectives on how to approach this from a personalized lens. Notable gaps remain on how one can precisely and prospectively select optimal treatment for patients based on varying risks, with an anticipation that an increased understanding of the biology of these different phenotypes and increasing refinement of imaging- and biomarker-based tools will, in time, allow these gaps to be closed

Culture Matters in Communicating the Global Response to COVID-19.

Current communication messages in the COVID-19 pandemic tend to focus more on individual risks than community risks resulting from existing inequities. Culture is central to an effective community-engaged public health communication to reduce collective risks. In this commentary, we discuss the importance of culture in unpacking messages that may be the same globally (physical/social distancing) yet different across cultures and communities (individualist versus collectivist). Structural inequity continues to fuel the disproportionate impact of COVID-19 on black and brown communities nationally and globally. PEN-3 offers a cultural framework for a community-engaged global communication response to COVID-19

Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma.

Follicular lymphoma (FL) is a common indolent B-cell lymphoma that can transform into the more aggressive transformed FL (tFL). However, the molecular process driving this transformation is uncertain. In this work, we aimed to identify microRNA (miRNA)-binding sites recurrently mutated in follicular lymphoma patients, as well as in transformed FL patients. Using whole-genome sequencing data from FL tumors, we discovered 544 mutations located in bioinformatically predicted microRNA-binding sites. We then studied these specific regions using targeted sequencing in a cohort of 55 FL patients, found 16 recurrent mutations, and identified a further 69 variants. After filtering for QC, we identified 21 genes with mutated miRNA-binding sites that were also enriched for B-cell-associated genes by Gene Ontology. Over 40% of mutations identified in these genes were present exclusively in tFL patients. We validated the predicted miRNA-binding sites of five of the genes by luciferase assay and demonstrated that the identified mutations in BCL2 and EZH2 genes impaired the binding efficiency of miR-5008 and miR-144 and regulated the endogenous levels of messenger RNA (mRNA)