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Introduction

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Diffuse large B cell lymphoma (DLBCL) is the commonest aggressive non-Hodgkin's lymphoma, accounting for approximately 4200 new cases annually in the UK.1 Standard of care rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) achieves cure in approximately 60% of cases.2 Patients who remain refractory or relapse have a poor outlook: around 20% event-free survival is recorded at 3 years.3 Attempts to intensify chemotherapy for high-risk subgroups have so far been unable to clearly recommend an improved, widely adopted approach. Recent advances surrounding molecular diagnostics reveal a heterogeneous disease that provides potential therapeutic targets to improve outcomes. DLBCL will likely require a personalized medicine approach to improve responses and survival for patients. Intensified chemotherapy regimens for high-risk subgroups, checkpoint inhibitors, monoclonal antibodies and small molecule agents represent opportunities to investigate and subsequently widen the armamentarium against DLBCL. Identification of predictive biomarkers to direct therapy will be necessary to unpick the complexity of this disease and guide subgroups towards precision therapy.

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Traditionally, DLBCL has been diagnosed by light microscopy and immunostaining of lymphoma tissue. Recent advances in molecular diagnostics have revealed marked heterogeneity and distinct subtypes. Through better characterization it is hoped that researchers can understand which features better confer immunochemotherapy resistance and identify targets for novel treatments. Gene expression profiling has revealed at least three distinct subtypes that represent clinically and biologically distinct entities.4 Potential targets of recurrent somatic point mutations have been identified through application of genome, exome and RNA sequencing, and more than 200 mutations have been found.

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Gene expression profiling and cell of origin

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Gene expression profiling is a technique to measure the relative expression of genes within a cell at the level of mRNA. Results reflect the range of cellular functions within DLBCL and have provided at least three distinct subgroups. The germinal centre B cell (GCB) subtype and the activated B cell (ABC) subtype represent the point in B cell ontogeny at which transformation to malignancy has occurred, known as the 'cell of origin'. The ABC subtype is characterized by chronic active B cell receptor signalling with constitutive activation of the nuclear factor kappa B (NFκB) pathway, whilst the GCB subtype involves genes in the germinal centre reaction. A third type, primary mediastinal B cell lymphoma (PMBL), has a different pattern of expression; other less well-defined subtypes also likely exist. Different cell-of-origin defined subtypes of DLBCL have significantly different frequencies of mutations: for example, CD79B and MYD88 are relatively common in ABC; mutations in genes involved in histone modification, including CREBBP and EZH2, are more common in GCB.5 There appears to be some clinical heterogeneity according to their molecular distinction. The ABC subtype is more commonly seen in older patients, is more likely to affect the nervous system, and in a retrospective analysis was found to have a worse prognosis and a reported overall survival of 40%.6 It is hoped that outcomes ...

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