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Updated: Jun 12, 2025
VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma
Published on: December 28, 2015
Large B-cell lymphomas with CCND1 rearrangement have different immunoglobulin gene breakpoints and genomic profile
Ece Özoğul1,2, Anna Montaner1, Melina Pol1
1Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Insights
Mantle cell lymphoma (MCL) typically has an IG::CCND1 translocation from V(D)J rearrangement. This study found CCND1 rearrangements in aggressive B-cell lymphomas can also arise from aberrant class-switch recombination or somatic hypermutation.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Mantle cell lymphoma (MCL) is defined by the IG::CCND1 translocation, usually from aberrant V(D)J recombination.
- CCND1 translocations in aggressive B-cell lymphomas, particularly SOX11-negative cases, are poorly understood.
- The genomic profiles and translocation mechanisms in these rare lymphomas are largely unknown.
Purpose of the Study:
- To investigate the mechanisms generating CCND1 rearrangements in SOX11-negative aggressive B-cell lymphomas.
- To determine the genomic profiles of these tumors.
- To expand the understanding of CCND1 alterations in B-cell malignancies.
Main Methods:
- Whole genome, exome, and targeted sequencing were used to analyze 13 SOX11-negative aggressive B-cell lymphomas.
- Reconstruction of IG::CCND1 translocations and detailed genomic profiling were performed.
- Analysis included identifying V(D)J rearrangement, class-switch recombination (CSR), and somatic hypermutation (SHM) events.
Main Results:
- Three tumors showed V(D)J-mediated IG::CCND1 translocations, including two blastoid MCL and one high-grade B-cell lymphoma.
- Ten tumors exhibited IGH::CCND1 translocations resulting from aberrant CSR or SHM mechanisms.
- These ten tumors were mainly large B-cell lymphomas with profiles distinct from MCL, including BCL6 rearrangements and mutations in KLF2, TNFAIP3, and KMT2D in two cases.
- Tumors with V(D)J translocations lacked a mutational profile typical of diffuse large B-cell lymphoma (DLBCL).
Conclusions:
- CCND1 rearrangements in aggressive B-cell lymphomas can arise from mechanisms beyond V(D)J recombination, notably aberrant CSR/SHM.
- These findings suggest CCND1 rearrangement can be a secondary event in the pathogenesis of DLBCL.
- The study highlights a distinct mutational landscape in these lymphomas compared to classical MCL.
Abstract:
Mantle cell lymphoma (MCL) is genetically characterized by the IG::CCND1 translocation mediated by an aberrant V(D)J rearrangement. CCND1 translocations and overexpression have been identified in occasional aggressive B-cell lymphomas with unusual features for MCL. The mechanism generating CCND1 rearrangements in these tumors and their genomic profile are not known. We have reconstructed the IG::CCND1 translocations and the genomic profile of 13 SOX11-negative aggressive B-cell lymphomas using whole genome/exome and target sequencing. The mechanism behind the translocation was an aberrant V(D)J rearrangement in three tumors and by an anomalous IGH class-switch recombination (CSR) or somatic hypermutation (SHM) mechanism in ten. The tumors with a V(D)J-mediated translocation were two blastoid MCL and one high-grade B-cell lymphoma. None of them had a mutational profile suggestive of DLBCL. The ten tumors with CSR/SHM-mediated IGH::CCND1 were mainly large B-cell lymphomas, with mutated genes commonly seen in DLBCL and BCL6 rearrangements in 6. Two cases, which transformed from marginal zone lymphomas, carried mutations in KLF2, TNFAIP3 and KMT2D. These findings expand the spectrum of tumors carrying CCND1 rearrangement that may occur as a secondary event in DLBCL mediated by aberrant CSR/SHM and associated with a mutational profile different from that of MCL.
