Mutations of multiple genes deregulate the NF-kB pathway in diffuse large B cell lymphoma

Description: Summary from the GEO "Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal center B cell-like (GCB) and activated B cell like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kB activation in these tumors represents an intrinsic program of the tumor cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations at multiple genes, including negative (TNFAIP3/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1 and TNFRSF11A/RANK) regulators of NF-kB. Of these, the A20 gene, which encodes for a ubiquitin-modifying enzyme involved in termination of NF-kB responses, is the most commonly affected one, with ~30% of the patients displaying biallelic inactivation by mutations and/or deletions, suggesting a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kB. Thus, our results demonstrate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, whose loss or activation may promote lymphomagenesis by leading to abnormally prolonged NF-kB responses.
We show that most ABC-DLBCL and a smaller fraction of GCB-DLBCL display genetic lesions affecting multiple NFkB pathway genes, with A20 representing the most frequently mutated gene
Keywords: Phenotypic characterization of human DLBCL.
DLBCL biopsies from 73 patients were collected from the archives of the Departments of Pathology at Columbia University and Weill Cornell Medical College. Total RNA was extracted from frozen tumor biopsies and processed according to Affymetrix standard protocols. Purified tonsillar geminal center, naive and memory B cells (5 samples each from different individuals) were purified by magnetic cell separation as described in Klein et al, PNAS 2003. The dataset includes also: 38 Follicular lymphoma biopsies and 5 lymphoblastoid cell lines."

Subject of Study

Homo sapiens

Subject(s)

Lymphoma, B-Cell

OncoTree Cancer Type(s)

Diffuse Large B-Cell Lymphoma, NOS

Access via GEO
TAR and CEL sequencing data.
Accession #: GSE12195

Access via BioProject
Additional information about overall initiative.
Accession #: PRJNA113415
Access Restrictions: Free to All
Access Instructions: The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications: Oricchio E, Katanayeva N, Donaldson M, et al. Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Science Translational Medicine. 2017; 9(396):eaak9969.
Data Type: Genomic
Equipment Used: Affymetrix Human Genome U133 Plus 2.0 Array
Software Used: GEO2R
Use GEO2R to compare two or more groups of Samples in order to identify genes that are differentially expressed across experimental conditions. Results are presented as a table of genes ordered by significance.
Dataset Format(s): TAR, CEL, RAW
Dataset Size: 811.4 Mb (TAR of CEL)

Data Catalog Record Updated: 2021-10-14