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- Study Description
Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de-novo diagnoses and also arising as a frequent clinical evolution of Follicular Lymphoma (FL). The molecular pathogenesis of DLBCL is associated with multiple genetic lesions that in part distinctly segregate with individual phenotypic subtypes, suggesting the involvement of distinct oncogenic pathways. However, the lesions identified so far likely represent only a fraction of those necessary for malignant transformation. In order to characterize the entire set of structural alterations present in the DLBCL genome, we have integrated next generation whole exome sequencing analysis of 7 DLBCL cases and genome-wide high-density SNP array analysis of 72 DLBCL cases. We report here that FL and DLBCL harbor frequent structural alterations inactivating CREBBP, and more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. Overall, ~37% of DLBCL and 36% of FL cases display genomic deletions and/or somatic point mutations that remove or inactivate the HAT coding domain of these two genes. These lesions commonly affect a single allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in the acetylation-mediated inactivation of the BCL6 onco-protein and activation of the p53 tumor suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-NHL, and have direct implications for the use of drugs targeting acetylation/deacetylation mechanisms.
- Study Type: Tumor vs. Matched-Normal
Number of study subjects that have individual level data available through Authorized Access: 77
- Authorized Access
- Publicly Available Data (Public ftp)
Connect to the public download site. The site contains release notes and manifests. If available, the site also contains data dictionaries, variable summaries, documents, and truncated analyses.
- Study Inclusion/Exclusion Criteria
- Previously untreated, de novo diagnoses of Diffuse Large B-cell Lymphoma.
- For the whole exome sequencing study, matched tumor and normal genomic DNA.
- Molecular Data
Type Source Platform Number of Oligos/SNPs SNP Batch Id Comment Whole Genome Genotyping Affymetrix AFFY_6.0 934940 52074 Whole Exome Sequencing Roche 454 GS FLX Titanium N/A N/A Exome Capture Roche High Density 2.1M Human Exome Array N/A N/A
- Selected publications
- Diseases/Traits Related to Study (MESH terms)
- Primary Phenotype: Lymphoma, Large B-Cell, Diffuse
- Authorized Data Access Requests
- Study Attribution
- Riccardo Dalla-Favera. Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
- Laura Pasqualucci. Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, USA
- PO1-CA-092625. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- RO1 CA-37295. National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Principal Investigators