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ID

45125

Description

Principal Investigator: Riccardo Dalla-Favera, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA MeSH: Lymphoma, Follicular,Lymphoma, Non-Hodgkin https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000328 *Version 1.* 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 6 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 oncoprotein and activation of the p53 tumor suppressor. These results identify *CREBBP/EP300* mutations as a major pathogenic mechanism shared by common forms of B-NHL, and have direct implications for the use of drugs targeting acetylation/deacetylation mechanisms. *Version 2.* Follicular lymphoma (FL) is an indolent, but incurable disease that, in 30-40% of cases, undergoes transformation to an aggressive diffuse large B cell lymphoma (DLBCL). The history of clonal evolution and the mechanisms that underlie transformation to DLBCL (tFL) remain largely unknown. Using whole exome sequencing and copy number analysis of 39 tFL patients, including 12 with paired sequential FL/tFL biopsies, we show that, in most cases, FL and tFL arise by divergent evolution from a common mutated precursor cell through the acquisition of distinct genetic lesions. Mutations in epigenetic modifiers (e.g., *MLL2, CREBBP, EZH2, ARID1A*) and anti-apoptotic genes (*BCL2, FAS*) were observed in 93% (36/39) and 78% (30/39) of cases, respectively, and were invariably shared between the two disease phases, suggesting an early acquisition in the common mutated precursor. Conversely, the development of tFL is associated with deregulation of genes involved in the control of cell proliferation, cell cycle progression and DNA damage responses (*CDKN2A/2B, MYC, TP53*), as well as with an aberrant activity of the somatic hypermutation mechanism. Finally, we show that the genomic profile of tFL shares significant similarities with that of germinal center B-cell type *de novo* DLBCL, but also displays unique combinations of altered genes that may explain the dismal clinical course of tFL. *Version 3. *This version includes thirty-five additional de novo DLBCL samples, newly diagnosed, and their paired normal DNA from previously untreated patients, which were analyzed by whole exome sequencing (n=27T and 25N), whole genome sequencing (8T and 10N), and/or targeted HLA-next generation sequencing (n=26T/N pairs) in order to identify genetic alterations associated with loss of surface MHC-II expression.

Link

https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000328

Keywords

  1. 9/20/22 9/20/22 - Simon Heim
  2. 10/12/22 10/12/22 - Adrian Schulz
Copyright Holder

Riccardo Dalla-Favera, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

Uploaded on

September 20, 2022

DOI

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License

Creative Commons BY 4.0

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    dbGaP phs000328 Genome-Wide Analysis of Diffuse Large B-Cell Lymphoma (De Novo and Derived from the High Grade Transformation of Follicular Lymphoma)

    Eligibility Criteria

    Inclusion and exclusion criteria
    Description

    Inclusion and exclusion criteria

    *Version 1.* Previously untreated, *de novo* diagnoses of Diffuse Large B-cell Lymphoma, nodal involvement.
    Description

    *Version 1.* Previously untreated, *de novo* diagnoses of Diffuse Large B-cell Lymphoma, nodal involvement.

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C0332155
    UMLS CUI [1,2]
    C0079744
    UMLS CUI [1,3]
    C1515568
    UMLS CUI [1,4]
    C0011900
    UMLS CUI [1,5]
    C0806692
    For the whole exome sequencing study, matched tumor and normal genomic DNA.
    Description

    For the whole exome sequencing study, matched tumor and normal genomic DNA.

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C4331441
    UMLS CUI [1,2]
    C3272453
    UMLS CUI [1,3]
    C0150103
    *Version 2.* Diffuse Large B-cell Lymphoma derived from the transformation of Follicular Lymphoma (tFL).
    Description

    *Version 2.* Diffuse Large B-cell Lymphoma derived from the transformation of Follicular Lymphoma (tFL).

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C0079744
    UMLS CUI [1,2]
    C1550535
    UMLS CUI [1,3]
    C0024301
    For 12 patients, longitudinal biopsies from the FL and tFL phase.
    Description

    For 12 patients, longitudinal biopsies from the FL and tFL phase.

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C0005558
    UMLS CUI [1,2]
    C0024301
    UMLS CUI [1,3]
    C2700204
    For 6 patients, matched normal DNA.
    Description

    For 6 patients, matched normal DNA.

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C0150103
    UMLS CUI [1,2]
    C3272453
    *Version 3.*Diffuse Large B-cell Lymphoma newly diagnosed, previously untreated.
    Description

    *Version 3.*Diffuse Large B-cell Lymphoma newly diagnosed, previously untreated.

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C0079744
    UMLS CUI [1,2]
    C1518321
    UMLS CUI [1,3]
    C0332155
    MHC-I positive and MHC-I negative cases   
    Description

    MHC-I positive and MHC-I negative cases   

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C0019629
    UMLS CUI [1,2]
    C1446409
    UMLS CUI [2,1]
    C0019629
    UMLS CUI [2,2]
    C0205160
    Matched normal DNA
    Description

    Matched normal DNA

    Data type

    boolean

    Alias
    UMLS CUI [1,1]
    C0681880
    UMLS CUI [1,2]
    C0012854

    Similar models

    Eligibility Criteria

    Name
    Type
    Description | Question | Decode (Coded Value)
    Data type
    Alias
    Item Group
    Inclusion and exclusion criteria
    *Version 1.* Previously untreated, *de novo* diagnoses of Diffuse Large B-cell Lymphoma, nodal involvement.
    Item
    *Version 1.* Previously untreated, *de novo* diagnoses of Diffuse Large B-cell Lymphoma, nodal involvement.
    boolean
    C0332155 (UMLS CUI [1,1])
    C0079744 (UMLS CUI [1,2])
    C1515568 (UMLS CUI [1,3])
    C0011900 (UMLS CUI [1,4])
    C0806692 (UMLS CUI [1,5])
    For the whole exome sequencing study, matched tumor and normal genomic DNA.
    Item
    For the whole exome sequencing study, matched tumor and normal genomic DNA.
    boolean
    C4331441 (UMLS CUI [1,1])
    C3272453 (UMLS CUI [1,2])
    C0150103 (UMLS CUI [1,3])
    *Version 2.* Diffuse Large B-cell Lymphoma derived from the transformation of Follicular Lymphoma (tFL).
    Item
    *Version 2.* Diffuse Large B-cell Lymphoma derived from the transformation of Follicular Lymphoma (tFL).
    boolean
    C0079744 (UMLS CUI [1,1])
    C1550535 (UMLS CUI [1,2])
    C0024301 (UMLS CUI [1,3])
    For 12 patients, longitudinal biopsies from the FL and tFL phase.
    Item
    For 12 patients, longitudinal biopsies from the FL and tFL phase.
    boolean
    C0005558 (UMLS CUI [1,1])
    C0024301 (UMLS CUI [1,2])
    C2700204 (UMLS CUI [1,3])
    For 6 patients, matched normal DNA.
    Item
    For 6 patients, matched normal DNA.
    boolean
    C0150103 (UMLS CUI [1,1])
    C3272453 (UMLS CUI [1,2])
    *Version 3.*Diffuse Large B-cell Lymphoma newly diagnosed, previously untreated.
    Item
    *Version 3.*Diffuse Large B-cell Lymphoma newly diagnosed, previously untreated.
    boolean
    C0079744 (UMLS CUI [1,1])
    C1518321 (UMLS CUI [1,2])
    C0332155 (UMLS CUI [1,3])
    MHC-I positive and MHC-I negative cases   
    Item
    MHC-I positive and MHC-I negative cases   
    boolean
    C0019629 (UMLS CUI [1,1])
    C1446409 (UMLS CUI [1,2])
    C0019629 (UMLS CUI [2,1])
    C0205160 (UMLS CUI [2,2])
    Matched normal DNA
    Item
    Matched normal DNA
    boolean
    C0681880 (UMLS CUI [1,1])
    C0012854 (UMLS CUI [1,2])

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