Seminar

Therapy driven by molecular diagnosis

Miguel Angel A. Piris, MD, PhD

Non-Hodgkin Lymphoma 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 tumour types and also enabled the detection of a number of targets with therapeutic implications, such as those activated downstream of the B/T-cell receptor. Our ability to identify the mechanisms involved in lymphoma pathogenesis has been boosted recently through the use of Next Generation Sequencing techniques in the analysis of human cancer. I will summarize the recent findings in the molecular pathogenesis of lymphoid 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. Analysing the current mutational data from a broader perspective, the results of NGS projects in B-cell lymphoma have essentially confirmed the taxonomy we currently apply in diagnosis, but at the same time several layers of complexity are being added to our understanding of lymphoma pathogenesis. Mutational rate and specific mutated pathways and genes may differ markedly within individual entities, as it has been recently shown in DLBCL, hence suggesting that therapeutic indications may require mutational signatures to be established case by case. Additionally, initial data are starting to show that at least some lymphoid neoplasms may carry a large number of microclones with rich complex dynamics throughout the life of the tumour, which may imply that mutational signatures need to be reinvestigated at different times during the life of the tumour in order to capture its changing nature. Lessons learned from solid and hematopoietic tumours suggest that the likely scenario for a more successful targeted therapy will be based in a combination of drugs targeting actionable mutated genes or deregulated pathways detected in major or minor clones within the tumour.