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BCL2 mutations in diffuse large B-cell lymphoma
J M Schuetz1, N A Johnson, R D Morin
1Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada.
Leukemia
|December 23, 2011
Summary
BCL2 mutations are frequent in germinal center B-cell DLBCL and follicular lymphoma, often occurring alongside translocations. These mutations, however, do not independently impact survival in DLBCL.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- BCL2 deregulation is a key event in diffuse large B-cell lymphoma (DLBCL), driven by translocations, amplification, or NF-κB signaling.
- Recent RNA-seq data highlight BCL2 as the most mutated gene in germinal center B-cell (GCB) DLBCL.
- Understanding BCL2 mutation patterns is crucial for diagnosing and treating B-cell lymphomas.
Purpose of the Study:
- To comprehensively analyze BCL2 gene mutations across various non-Hodgkin lymphoma subtypes.
- To investigate the correlation between BCL2 mutations, translocations, and clinical outcomes in DLBCL.
- To determine the impact of BCL2 mutations on protein expression in DLBCL.
Main Methods:
- Sequencing of the BCL2 gene in 298 primary DLBCL biopsies, 131 other non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines, and 51 germline DNAs.
- Analysis of mutation frequency, type, and location within the BCL2 gene.
- Assessment of the relationship between BCL2 mutations, translocations, and patient survival.
- Evaluation of BCL2 protein expression in relation to mutations.
Main Results:
- Frequent BCL2 mutations were observed in follicular lymphoma (FL) and GCB DLBCL.
- Low frequencies of BCL2 mutations were found in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia, and peripheral T-cell lymphoma.
- No BCL2 mutations were detected in germinal center centroblasts.
- Mutations were predominantly non-synonymous, located in the flexible loop domain, and consistent with somatic hypermutation.
- BCL2 translocations correlated with additional BCL2 mutations in GCB DLBCL and FL.
- BCL2 mutations were not independently associated with survival in DLBCL.
- Pseudo-negative BCL2 protein expression due to mutations was rare in de novo DLBCL.
Conclusions:
- BCL2 mutations are a common feature of GCB DLBCL and FL, often associated with translocations and somatic hypermutation.
- The presence of BCL2 mutations does not appear to be an independent prognostic factor for survival in DLBCL.
- While BCL2 mutations can occur, they rarely lead to pseudo-negative protein expression in de novo DLBCL, unlike in FL.
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