The role of next-generation sequencing in understanding the genomic basis of diffuse large B cell lymphoma and advancing targeted therapies

ABSTRACT

Next Generation Sequencing (NGS) has redefined the genetic landscape of Diffuse Large B-Cell Lymphoma (DLBCL) by identifying recurrent somatic mutations. Importantly, in some cases these mutations impact potentially actionable targets, thus affording novel personalized therapy opportunities. At the forefront of today’s precision therapy era, how to best incorporate NGS into daily clinical practice is of primordial concern, in order to tailor patient’s treatment regimens according to their individual mutational profiles. With the advent of cell-free DNA sequencing, which provides a sensitive and less invasive means of monitoring DLBCL patients, the clinical feasibility of NGS has been greatly improved. This article reviews the current landscape of DLBCL mutations, as well as the targeted therapies developed to counter their effects, and discusses how best to utilize NGS data for treatment decision-making.

KEYWORDS:

• Next Generation Sequencing
• Diffuse Large B-Cell Lymphoma
• targeted therapy
• actionable target
• molecular multidisciplinary meeting
• cell-free DNA

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• NGS has provided new insights into the genomic characterization of DLBCL, notably by identifying recurrent SNVs, which can impact actionable targets.

• DLBCL mutational landscapes are subtype-specific, with GCB subtype characterized by mutations targeting epigenetic-related genes and ABC subtype characterized by mutations targeting the NF-κB pathway.

• The mutational profile of PMBL has identified highly recurrent driver mutations leading to JAK-STAT pathway activation (SOCS1, STAT6, and PTPN1), suggesting that NGS might be of great interest to improve PMBL diagnosis accuracy, notably in cases without mediastinal involvement.

• The ABC-type mutational profiles of DLBCL-LT and DLBCL in immune-privileged sites suggest that ibrutinib-based combinations are likely to represent promising therapeutic options for these subtypes.

• Certain recurrently mutated genes have been shown to confer inferior prognosis in DLBCL patient cohorts, including MYD88, FOXO1, and TP53 mutations.

• EZH2, KMT2D, EP300, and CREBBP mutations are highly frequent, mainly in GCB subtype DLBCL, leading to transcriptional repression, and can potentially be targeted by combination strategies, including EZH2, BCL2, HDAC, and histone demethylase inhibitors.

• Inhibitors targeting BCR and NF-κB pathway mutations (i.e. PI3K, BTK, and PKC inhibitors) are dependent on chronic active BCR signaling; NF-κB pathway mutations, such as CD79B and MYD88 mutations, are predictive of patient response.

• Developing consensus targeted NGS panels and including NGS data in molecular multidisciplinary meetings without delaying first-line treatment is crucial to developing personalized therapy in DLBCL.

• cfDNA NGS is highly specific and minimally invasive, capable of determining MRD as well as non-immunoglobulin somatic mutations, validating the concept of liquid biopsy in DLBCL.