B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

Abstract

B-cell lymphomas comprise an increasing number of clinicopathological entities whose characterization has historically been based mainly on histopathological features. In recent decades, the analysis of chromosomal aberrations as well as gene and miRNA expression profile studies have helped distinguish particular tumor types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B-cell receptor. Our ability to identify the mechanisms involved in B-cell lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. This work summarizes the recent findings in the molecular pathogenesis of B-cell neoplasms with special focus on those clinically relevant somatic mutations with the potential to be explored as candidates for the development of new targeted therapies. Our work includes a comparison between the mutational indexes and ranges observed in B-cell lymphomas and also with other solid tumors and describes the most striking mutational data for the major B-cell neoplasms. This review describes a highly dynamic field that currently offers many opportunities for personalized therapy, although there is still much to be gained from the further molecular characterization of these clinicopathological entities.

Figure 1.

Somatic mutations affecting B-cell lymphomas. The bar graph shows the mutational indexes (MIs) of B-cell lymphoma studies compared with selected studies reflecting those of solid tumours. MI indicates the number of mutations (possibly affecting protein activity) per Megabase (Mb), assuming the size of the human exome to be 30 Mb. The table shows the MI, range, percentage of transitions and transversions, sample size and type of mutational analysis: whole exome sequence (WES), whole genome sequence (WGS), mRNA-seq. (c) indicates cell lines used. (u) indicates untreated. Table 1. Data supporting Figure 1. Mutational Indexes (MI), range, percentage of transitions and transversions, sample size and type of mutational analysis: whole exome sequence (WES), whole genome sequence (WGS), mRNA-seq. (c) indicates cell lines used. *Focused on mutations affecting protein function.

Figure 2.

Principal inhibitors of BCR downstream signaling. Principal signaling pathways activated downstream of BRC and its associated co-receptors. Brown: CD19-mediated PI3K/mTOR activity; Blue: MAPK activation; Red: BTK/PLC downstream activity and signaling through secondary messengers (Ca²⁺ and DAG); Purple: Toll-like receptors/Myd88 activation of NFKB; Pink: direct specific inhibitors of potential use in targeted therapy for B-cell lymphomas.