Large B-cell lymphomas with CCND1 rearrangement have different immunoglobulin gene breakpoints and genomic profile than mantle cell lymphoma

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.

Fig. 1. IG and CCND1 breakpoints.

A Schematic representation of the location of the breakpoints found in the IG loci (IGH, top, IGL, bottom). CSR, class-switch recombination region. IGHJ genes (1–6) are shown as a single gene due to their small size and compactness for illustrative purposes. Genomic locations are shown on the x axis. Breakpoints are colored based on their underlying mechanism as AID-mediated through aberrant CSR/SHM or RAG-mediated during the initial J-D recombination. B Representation of the breakpoints found in chromosome 11. MTC major translocation cluster.

Fig. 2. Profile of putative driver mutations in CCND1-R neoplasms.

Oncoprint showing the morphology, SOX11 status, presence/absence of IG::CCND1, IGHV identity, NGS and FISH studies performed, and putative driver gene mutations found in the studied samples. Cases are grouped based on the mechanism underlying the IG::CCND1 rearrangement. *, Cryptic BCL6 rearrangement only identified by WGS.

Fig. 3. Blastoid MCL lymphoma with RAG-mediated CCND1 rearrangement.

A The tumor cells are predominantly medium to large size with round nuclei and blastoid chromatin. Smaller cells with irregular nuclei are also present (H&E stain, original magnification ×400). B Cyclin D1 immunohistochemical staining shows expression in all range of tumor cells (immunoperoxidase, original magnification ×400).

Fig. 4. SMZL and transformed LBCL with CSR-mediated CCND1 rearrangement.

A Splenic marginal zone lymphoma with expansion of the marginal areas of the white pulp (H&E stain, original magnification ×100). B Cyclin D1 staining was negative (immunoperoxidase, original magnification ×200). C Lymph node with diffuse large B-cell lymphoma obtained 14 years later. Both tumors had the same clonal IGHV1-2*04 - IGHD3-10*01 - IGHJ6*02 rearrangement (H&E stain, original magnification ×200). D The transformed tumor was positive for cyclin D1 in the large cells but also in occasional atypical smaller cells (immunoperoxidase, original magnification ×200).

Fig. 5. Radiological, Morphological and FISH findings in a large B-cell lymphoma with IRF4 and CCND1 rearrangement (Patient #8).

A Computed tomography (CT)-scan demonstrates a large mass in the stomach that was biopsied. B Panoramic view of the gastric biopsy obtained at relapse with a diffuse lymphoid infiltration in one of the fragments. (hematoxylin and eosin (H&E) stain, original magnification, ×50). C Higher magnification shows that the tumor is composed or medium to large-sized lymphoid cells with irregular nuclei, blastic chromatin, inconspicuous nucleoli and clear cytoplasm. (H&E stain, original magnification ×400). D Giemsa stain highlights the blastic cytology of the lymphoid cells (Giemsa stain, original magnification, ×400). E The tumor cells are positive for CD20, CD10 (F), BCL6 (G), MUM1/IRF4 (H), and cyclin D1 (I). (immunoperoxidase, original magnification ×400). J The MIB1/Ki67 stain shows a proliferation index of 100%. K FISH analysis using an IRF4 break-apart assay demonstrates a signal constellation of one colocalized signal (inset, yellow arrow) and one split signal (inset, red and green arrows) consistent with gene rearrangement. L FISH analysis using an CCND1 break-apart assay shows a signal constellation of one colocalized signal (inset, yellow arrow) and one split signal (inset, red and green arrows) consistent with gene rearrangement.