Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma

Abstract

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level, but other less common subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 755 B-NHL tumors at high depth; primarily including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated across major subtypes, such as the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations that are pathognomonic. The cumulative burden of mutations within a single cluster were more significantly discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic epistasis that contribute to disease etiology. We therefore provide a framework of co-occurring mutations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis of B-NHL subtypes.KEY POINTSGenetic perturbation of the ubiquitin proteasome system is an emerging hallmark of B-cell non-Hodgkin lymphoma (B-NHL).Co-occurring sets of genetic alterations define B-NHL subtypes and likely represent epistatic interactions.

TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-tumorigenic Memory Fate

“…We immunized Tbl1xr1 D370Y/WT (D370Y/WT) or Tbl1xr1 WT/WT (wild-type [WT]) mice with the T cell-dependent antigen sheep red blood cells (SRBC) and sacrificed them at the peak of the GC reaction. Unexpectedly, although B cell abundance remained unaltered in D370Y/WT mice (Figure 1C; Data S1D and S1E), these animals showed significant decrease in the absolute number (p value = 0.0008; Data S1E) and proportion (Arthur et al, 2018;Ma et al, 2019;Reddy et al, 2017) and FL (Krysiak et al, 2017;Ma et al, 2019;Ortega-Molina et al, 2015). TBL1XR1-SMRT interacting region (Zhang et al, 2002) and PPI mutated positions are indicated.…”

“…Information on TBL1XR1 mutation status in human lymphoma specimens was retrieved from publicly available datasets. DLBCL cases (Arthur et al, 2018;Ma et al, 2019;Reddy et al, 2017;Schmitz et al, 2018); FL cases: (Krysiak et al, 2017;Ma et al, 2019;Ortega-Molina et al, 2015). Clinic-pathological characteristics of these cases are detailed in the original publications.…”

UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells

“…However, mutations within the HECT domain were found only in MCL tumors ( Figure 1A). 3 Patients with UBR5 mutations had between 4 and 12 additional mutations, but did not significantly cooccur with other mutations ( Figure 1B). 3 These findings suggest that HECT domain mutations of UBR5 are a disease-specific genetic feature of MCL.…”

“…Recently, monoallelic mutations in the ubiquitin protein ligase E3 component n-recognin 5 (UBR5) were found in ;18% of patients with MCL. 3,4 Approximately 60% of mutations identified in UBR5 were frame shift mutations within its HECT domain, which can accept and transfer ubiquitin molecules to the substrate, leading to a premature stop codon before the cysteine residue associated with ubiquitin transfer.…”

Harnessing lymphoma epigenetics to improve therapies

“…More recently, studies have revealed additional transcription factors, corepressor/coactivator complex components, histone-modifying enzymes, chromatinremodeling complex components, and chromatin structural components that are targeted by genetic alterations in B-cell lymphoma. These alterations differ in frequency between histologies 1 and/or within transcriptionally or genetically defined subtypes, 2,3 function by perturbing epigenetic and transcriptional programs that control cellular pathways and cell fate decisions that are important for the tumor's cell of origin (reviewed elsewhere [4][5][6], and are potentially targetable by an increasing number of epigenetic-modifying agents. 7 Therefore, understanding the epigenetic basis for lymphoma is an important challenge due to the high potential for clinical translation that could improve patient outcomes.…”