The activity of the Translational Hematopathology group focuses on:
- Development of translational research projects in clinical trials with new drugs for patients with lymphoma.
- Tune-up and clinical validation of new technologies for the molecular diagnosis of patients with hematolymphoid neoplasms. Liquid biopsy for the genotyping of cases of LBDCG included in prospective clinical trials.
Currently, a line of advancement of our group is the optimization of a genotyping protocol from free circulating tumor DNA in plasma (liquid biopsy) of patients with diffuse B-cell Large Lymphoma. We have recently demonstrated the feasibility and usefulness of this technology in patients included in a multicentre clinical trial promoted by the GELTAMO group (Cell Free Tumor DNA for DLBCL Genotyping in a Phase II Randomized Trial Comparing Standard RCHOP Versus Brcap As First Line Treatment in Patients with Poor IPI DLBCL). Figure 1A.
Our group, complete with the HUMV pathology service, leads a centralized molecular and anatomopathological diagnostic platform for the clinical trial samples for patients with diffuse large cell lymphoma B from the national cooperative group GELTAMO (Spanish Lymphomas Group and Transplant Bone marrow, GELBRCAP21 (No. EudraCT: 2012-005138-12), GEL-RCOMP 2013 (No. EudraCT: 2013-001065-17), LR-ESHAP (No. EudraCT: 2010-018463-41), IBDCL (No. EudraCT: 2015 -005390-21) This project has funding from national funds (MINECO, PI16 / 1397) Identification of genetic alterations involved in the pathogenesis of large cell B-cell lymphoma and its progression.
Diffuse large-cell lymphoma B (LBDCG) is the most common form of non-Hodgkin's lymphoma in our country and accounts for 80% of aggressive lymphomas, with an upward-trend incidence that represents about 93,000 new cases a year in Europe. (GLOBOCAN (IARC) The precise subclassification of the different entities of LBDCG has clinical relevance from the point of view of prognosis and selection of therapy since there are a series of phenotypes of aggressive clinical behavior (high grade B lymphoma with "double / triple hit ", ABC subtype LBDCG, plasmablastic lymphoma) for which standard immunochemotherapy is ineffective Recent studies using massive sequencing of the genome and the exome are identifying recurrent genetic alterations in the NFkB, BCR, JAK / STAT pathways, modifying genes of histones and genes related to the immune response, among others Some of these alterations are associated with specific phenotypes and can be targeted therapy targets.
Recent data from our group (S Montes-Moreno, et al.Modern Pathology 2017) reinforce the relevance of the MYC oncogene in plasmablastic lymphoma and describe, for the first time, somatic mutations in PRDM1 / blimp1 in this type of neoplasm, revealing new molecular mechanisms of the disease (Figure 1B). The recent implementation of NGS-directed sequencing technologies in cases of LBDCG is revealing that mutational profiles are associated with specific clinicopathological variants and condition their phenotype. Recent observations from our group confirm that the application of directed sequencing methods of the exome using NGS allows to trace the clonal evolution of the refractory LBDCG and may have an impact on the selection of the optimal therapy (Garcia-Reyero et al., Clonal Evolution in primary diffuse large B cell lymphoma of the Central Nervous System, AIMM, 2018, epub) (Figure 1C).
Figure 1. A. Diagram of the genotyping process using NGS from Liquid Biopsy. B. The molecular characterization of plasmablastic lymphoma allows to explain the interaction between neoplasm driver genes (MYC) and other regulatory genes (PRDM1 / Blimp1) revealing new molecular mechanisms of the disease (Plasmablastic lymphoma phenotype is determined by genetic alterations in MYC and PRDM1 Modern Pathology 2017). C. The new methods of directed sequencing of the exome using NGS allow to trace the clonal evolution of the refractory LBDCG (Clonal Evolution in primary diffuse large B cell lymphoma of the Central Nervous System, AIMM, 2018).