Decoding the genetic landscape of pediatric and young adult germinal center-derived B-cell non-Hodgkin lymphoma

Abstract

B-cell non-Hodgkin lymphoma (B-NHL) of pediatric and young adult population is a diverse group of neoplasms predominantly composed of aggressive B-cell lymphomas from the germinal center (GC). Molecular characterization of pediatric series has allowed the identification of several subtypes that predominantly occur in this subgroup of age. Despite of that, genomic features of these pediatric entities and their relationship to other B-NHL in this group of patients have not been extensively investigated. This thesis has aimed to address this gap of knowledge by performing a genetic and molecular characterization of large series of pediatric and young adult variants of GC-derived B-NHL including the Burkitt- like lymphoma with 11q aberration (BLL-11q) , pediatric type follicular lymphoma (PTFL) and large B-cell lymphomas (LBCL) such as diffuse large B-cell lymphomas (DLBCL) , high grade B- cell lymphomas, not otherwise specified (HGBCL, NOS) and large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) entities.

In the Study 1 we have molecularly characterized a series of 11 BLL-11q observing that BLL- 11q differed clinically, morphologically and immunophenotypically from conventional BL and instead showed features more consistent with HGBCL or DLBCL. Genomic profile was also different from that of BL and DLBCL with a mutational landscape characterized by the lack of typical BL mutations in ID3, TCF3, or CCND3 genes and recurrent specific BTG2 and ETS1 mutations, not present in BL but in germinal center B-cell (GCB) DLBCL subtype. All these observations suggest that BLL-11q is a neoplasm closer to other GC-derived lymphomas rather than BL. In Study 2, we expanded our knowledge on the genetic alterations associated to PTFL by verifying the presence of MAP2K1 and IRF8 mutations in a previously well characterized series of 43 PTFL. We demonstrate the activating effect of MAP2K1 mutations by immunohistochemical analysis observing phosphorylation of the MAP2K1 downstream target extracellular signal-regulated kinase in those mutated cases. Besides, we demonstrate the specificity of MAP2K1 and IRF8-K66R mutations since they are absent in conventional FL or in t(14;18)-negative FL. Finally, in the Study 3 we characterized a large series of LBCL including DLBCL, HGBCL, NOS and LBCL-IRF4 through an integrative analysis including targeted next generation sequencing, copy number, and transcriptome data. Results showed that each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B) whereas DLBCL, NOS was predominantly of GCB-DLBCL subtype and carried gene mutations similar to the adult counterpart (e.g., SOCS1 and KMT2D). A subset of HGBCL, NOS displayed recurrent alterations of BL-related genes such as MYC, ID3, CCND3 and SMARCA4, whereas other cases were genetically closer to GCB-DLBCL. Interestingly, we could identify age-related differences in pediatric DLBCL since pediatric and young adult cases were mainly of GCB subtype, displayed low genetic complexity and virtually lacked primary aberrations (BCL2, MYC and BCL6 rearrangements). Finally, we identify clinical and molecular features related to unfavorable outcome such as age >18 years, high LDH levels, activated B-cell (ABC) DLBCL profile, high genetic complexity, homozygous deletions of 19p13.3/TNFSF7/TNFSF9, gains of 1q21-q44/MDM4/MCL1 and TP53 mutations.

Altogether, we conclude that GC-derived B-NHL of pediatric and young adult population is a heterogeneous group of tumors including different entities with specific molecular profiles and clinical behavior. This thesis has contributed to increase the knowledge of these lymphoma entities identifying biomarkers that might be helpful to improve their diagnosis and to design management strategies more adapted to their particular biological behavior.