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Title: Genome-wide Analysis of Lymphoma      
citations:
19412164
21390126
21156281
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.
Identifier:
phs000328.v1.p1
accesstypes:
download
enclave
landingpage: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000328.v1.p1
authentication: simpleLogin
none
authorization:
none
duaIndividual
name:
Lymphoma, Large B-Cell, Diffuse
affiliations:
Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
name:
Riccardo Dalla-Favera
roles:
Principal Investigators
affiliations:
Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, USA
name:
Laura Pasqualucci
roles:
Principal Investigators
affiliations:
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
name:
PO1-CA-092625
roles:
Funding Source
affiliations:
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
name:
RO1 CA-37295
roles:
Funding Source
performedBy:
TitleNameInstitute Principal InvestigatorsRiccardo Dalla-FaveraInstitute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA Principal InvestigatorsLaura PasqualucciInstitute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, USA Funding SourcePO1-CA-092625National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Funding SourceRO1 CA-37295National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
downloadURL: https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?page=DUC&view_pdf&stacc=phs000328.v1.p1
Identifier:
phs000328.v1.p1_policy
name:
Data Use Certificate
Identifier:
1
name:
Cancer Research and Methods
alternateIdentifiers:
yes
selectionCriteria:

  1. Previously untreated, de novo diagnoses of Diffuse Large B-cell Lymphoma.
  2. For the whole exome sequencing study, matched tumor and normal genomic DNA.

types:
Tumor vs. Matched-Normal
dateReleased:
11-22-2010
version:
phs000328.v1.p1
dateModified:
03-22-2011
abbreviation:
eNCI DAC
name:
Extramural NCI Data Access Committee
ID:
0
name:
dbGaP

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